(Circulation. 1998;98:2037-2042.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports |
Influence of the Angiotensin II Antagonist Valsartan on Left Ventricular Hypertrophy in Patients With Essential Hypertension
From the Philipp Klee-Institute of Clinical Pharmacology, Hospital Wuppertal GmbH, Clinical Pharmacology, University Witten/Herdecke, Wuppertal (P.A.T.); Institute of Clinical Pharmacology, University Hospital, Frankfurt (S.H., N.R.); Department of Internal Medicine, Diakonissenkrankenhaus, Frankfurt (P.K.); and General Practice, Offenbach/Main (A.S.), Germany.
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Abstract |
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Background—Left ventricular hypertrophy (LVH) represents an independent risk factor in patients with essential hypertension. Because reversal of LVH may be associated with an improvement of prognosis, the influence of new antihypertensive compounds, such as angiotensin II AT1 receptor antagonists, on LVH should be determined.
Methods and Results—In a randomized, double-blind trial, 69 predominantly previously untreated hypertensive patients with echocardiographically proven LVH, ie, left ventricular mass index (LVMI) >134 g/m2 in men and >110 g/m2 in women and/or end-diastolic septal thickness >12 mm, received either the angiotensin II antagonist valsartan or atenolol for 8 months. Echocardiographic data of 58 patients were available. After 8 months of valsartan treatment (n=29), LVMI decreased from 127±23 to 106±25 g/m2 (ratio [R]=0.83; 95% CI, 0.79 to 0.87; P<0.0001 versus baseline). Under atenolol (n=29), LVMI decreased to a smaller extent, from 127±25 to 117±27 g/m2 (R=0.92; 95% CI, 0.86 to 0.98; P=0.0082 versus baseline). The mean reduction of LVMI came to 21 g/m2 under valsartan and only to 10 g/m2 under atenolol (R=0.91; 90% CI, 0.85 to 0.97 versus atenolol). Baseline mean blood pressure values were determined to be 163±12/101±6 mm Hg before treatment with valsartan and 160±14/103±6 mm Hg before atenolol treatment. After 8 months of treatment, mean blood pressure decreased to 146±13/90±7 mm Hg with valsartan and to 147±18/90±7 mm Hg with atenolol. Nine patients in the valsartan group and 8 patients in the atenolol group required additional medication with hydrochlorothiazide.
Conclusions—Antihypertensive treatment with the angiotensin II antagonist valsartan for 8 months produced a significant regression of LVH in predominantly previously untreated patients with essential hypertension. The drug may be safely administered in this subset of hypertensive patients; however, the long-term benefit in terms of risk reduction has still to be evaluated in further trials.
Key Words: hypertension • hypertrophy • ventricles • angiotensin
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Introduction |
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In hypertensive patients, left ventricular hypertrophy (LVH) represents a powerful predictor for cardiovascular morbidity and mortality independent of other cardiovascular risk factors, even blood pressure itself.1 2 Regression of LVH may be associated with an improvement of prognosis.3 4 Meta-analyses5 6 and a recently published trial7 comparing the effects of different drug classes on LVH have suggested that ACE inhibitors are currently the most powerful drugs in this regard. In contrast, recently published prospective trials comparing the effects of different drug classes revealed no relevant differences in terms of LVH reduction,7 8 and the question of whether antihypertensive drugs differ in their ability to regress LVH was put forward.9 Considering the importance of LVH as an independent risk factor, the safety and efficacy of new antihypertensive drugs in patients with LVH have to be studied.
In addition to a chronic increase in pressure and/or volume overload, an elevation in plasma ACE activity, plasma aldosterone levels,10 and angiotensin II (Ang II) concentrations play a major role in the development of LVH.11 Reduction of Ang II levels after ACE inhibition may be responsible for the beneficial effects of ACE inhibitors beyond the blood pressure–lowering activity. Apart from cleavage of Ang I by ACE, alternative pathways exist for the formation of Ang II, and despite ACE inhibition, a considerable amount of Ang II may be present, particularly in the heart.12 Because almost all known actions of Ang II are mediated via the AT1 receptor subtype,13 the recently introduced specific Ang II AT1 receptor antagonists could also be useful drugs in terms of LVH regression.14 Experimental data suggest a considerable effect of this class of drugs on myocardial hypertrophy and fibrosis.15 16
The antihypertensive efficacy of the selective Ang II antagonist valsartan17 in essential hypertensive patients was shown earlier.18 We investigated the influence of 8 months of antihypertensive treatment with this Ang II antagonist on LVH versus the ß-adrenergic receptor antagonist atenolol. ß-Adrenergic receptor antagonists are included as first-line treatment in the recommendations of most national and international committees for the treatment of high blood pressure. Atenolol has recently been shown to be at least equally tolerable and to ensure blood pressure control comparable to that with enalapril, hydrochlorothiazide (HCTZ), and nitrendipine.19 We enrolled predominantly untreated patients to avoid the effects of previous drug treatment.
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Methods |
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Patients and Study Design
The trial followed a randomized, double-blind, actively controlled, parallel-group design.20 The study protocol was approved by the ethics committee of the University Hospital in Frankfurt, and all study participants gave written informed consent before participation in the trial. Patients were recruited and treated by 14 general practitioners, whereas echocardiographic readings and analyses were performed at 1 central laboratory (P.K.).
One hundred seventeen previously untreated, white, hypertensive patients or those who had been treated (1) for <4 weeks during the previous 12 months or (2) with diuretics only were screened. Secondary forms of hypertension were excluded. Pretreatment with diuretics was considered acceptable, because their effect on left ventricular mass and especially wall thickness parameters has been shown to be negligible.6 21 Normal renal and liver function tests as well as blood counts were confirmed in 1 central laboratory.
The inclusion criterion was a diastolic blood pressure between 95 and 115 mm Hg and systolic blood pressure between 150 and 180 mm Hg determined after a single-blind, 3-week placebo run-in period. All blood pressure measurements were performed in duplicate with a standard cuff sphygmomanometer after 10 minutes in the sitting position. During the run-in period, the presence of LVH was established by echocardiography and defined as left ventricular mass index (LVMI) >134 g/m2 body surface area for men and >110 g/m2 for women and/or septal thickness >12 mm at end diastole.22
Randomized patients received, in a double-blind manner, either valsartan 80 mg/d or atenolol 50 mg/d for the following 4 weeks. If blood pressure was not adequately controlled, ie, sitting diastolic blood pressure measured in the morning before drug intake >95 mm Hg, the dose of both drugs was doubled. After an additional 4 weeks, HCTZ could be added in those patients in whom diastolic blood pressure still exceeded 95 mm Hg. After 3 months, the second echocardiogram was performed; regular visits were then at 8-week intervals. The final visit and third echocardiogram were performed after 8 months of double-blind treatment.
Echocardiography
All echocardiographic recordings were
performed by 1 experienced investigator using a Hewlett Packard Sonos
1000 system with a 2.5-MHz transducer according to recommendations of
the American Society of
Echocardiography.23 M-mode
recordings were guided by 2-dimensional views. LVMI was
calculated according to the formula of Devereux et
al.22 Left ventricular
end-diastolic and end-systolic volumes were
determined by 2-dimensional echocardiography, and
left ventricular ejection and fractional shortening were
calculated with standard formulas. Pulsed-wave Doppler
recordings of transmitral flow velocity were performed to
calculate the areas under the velocity/time curves 
E and
A.
Values from at least 3 beats were measured and averaged, and intraobserver variability was determined to be 6.8%, 6.2%, 3.8%, and 13% for end-diastolic septal thickness, end-diastolic posterior wall thickness, left ventricular internal diameter, and VmaxE/VmaxA, respectively.24
Statistical Analysis
For primary efficacy analysis, baseline and final LVMIs
were compared within treatment groups. To detect a clinically relevant
change of 
15% with 80% power, 26 patients were required in each
treatment group, assuming a coefficient of variation of 29% and using
Student's t test on logarithmically transformed
data. The level of significance was set to 5%. To compare the change
in LVMI between groups, the 90% CI of the 2 ratios could be calculated
with a precision of ±13%.
For the intention-to-treat analysis, all randomized patients having at least 1 postbaseline echocardiogram were included. The primary efficacy variable LVMI and secondary variables were analyzed after logarithmic transformation of the data by the paired t test (SAS), and the corresponding 95% CIs were calculated.
Between-treatment differences were analyzed by ANCOVA, and 95% CIs were derived. Data are given as mean±SD; if appropriate, the median value is quoted.
A correlation analysis (Kendall) was performed between percent
reduction in systolic and diastolic blood
pressures, respectively, and change in LVMI. Kendall correlation
coefficients (
) and corresponding P values are given.
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Results |
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Patients
One hundred seven patients underwent a baseline echocardiogram; 69 met the inclusion criteria (Table 1
). The known duration of
hypertension was maximally 8 years (median, 17 months). Two patients
were pretreated with diuretics, and 11 patients had received
other blood pressure–lowering drugs for <4 weeks in the 12 months
before the study. Concomitant diagnoses and medications are given in
Table 2. In addition, 9 patients received
acetylsalicylic acid and paracetamol for relief of
common cold symptoms.
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Three patients in each treatment group discontinued the study because of adverse events: under valsartan, 1 female patient developed a probably drug-induced bilateral dermatitis of the breast, 1 patient had a subarachnoid hemorrhage, and in 1 patient a brain tumor was diagnosed. Under atenolol, 2 patients experienced angina and 1 patient dyspnea, the latter possibly associated with atenolol. Safety blood chemistry parameters revealed no variations in the mean and median values, especially for serum creatinine and urea, as well as blood lipid profiles, with the exception of 1 patient receiving atenolol 100 mg/d plus HCTZ, in whom a clinically relevant increase of serum uric acid, creatinine, and urea occurred.
Fifty-eight patients (n=29 in each treatment group) were evaluable for the intention-to-treat analysis of LVH; echocardiographic data and blood pressure values for these patients are presented.
Blood Pressure Control
In the valsartan treatment group, a dose increment to 160 mg/d was
required in 14 patients, and 9 patients required additional medication
with HCTZ. In the atenolol group, 16 patients received 100 mg/d, and in
8 patients, addition of HCTZ was necessary to achieve a satisfactory
blood pressure control.
After 8 months of valsartan treatment, systolic blood pressure decreased from 163±12 to 146±13 mm Hg (mean, –17 mm Hg; 95% CI, –21 to 13 mm Hg; P<0.0001), diastolic blood pressure decreased from 101±6 to 90±7 mm Hg (mean, –11 mm Hg; 95% CI, –14 to 8 mm Hg; P<0.0001). Treatment with atenolol resulted in a decrease of systolic blood pressure from 160±14 to 147±18 mm Hg (mean, –13 mm Hg; 95% CI, –18 to 7 mm Hg; P<0.0001), and diastolic blood pressure was reduced from 103±6 to 90±7 mm Hg (mean, –12 mm Hg; 95% CI, –15 to 9 mm Hg; P<0.0001).
Heart rate remained almost unchanged under valsartan treatment at 76 bpm (median value) before treatment and 73 bpm after 8 months of treatment, whereas under atenolol, an expected marked decrease from 76 to 64 bpm was observed.
Echocardiographic Data
After 3 months of valsartan therapy, LVMI decreased slightly, from
127±23 to 119±23 g/m2, whereas a significant
decrease could be observed after 8 months to 106±25
g/m2 (R=0.83; 95% CI, 0.79 to 0.87;
P<0.0001 versus baseline). In the atenolol group, LVMI
decreased from 127±25 to 119±23 g/m2 during the
first 3 months; after 8 months, LVMI was determined to be 117±27
g/m2 (R=0.92; 95% CI, 0.86 to 0.98;
P=0.0082 versus baseline; Figure 1). Covariate analyses revealed
no influence of sex and age on treatment effects.
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The mean reduction of LVMI was 21 g/m2 under valsartan and 10 g/m2 under atenolol (R=0.91; 90% CI, 0.85 to 0.97 versus atenolol), suggesting a tendency toward a more pronounced treatment effect with valsartan.
Septal and posterior wall thicknesses were reduced by both drugs,
valsartan being slightly more effective (Table 3). Left ventricular internal
diameters and volumes and their derived parameters ejection
fraction and fractional shortening remained almost constant (Table 3).
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No relevant changes were observed for Doppler
echocardiographic parameters (Table 4); the ratio E/A showed a small
but significant increase after atenolol treatment (R=1.18;
95% CI, 1.05 to 1.33; P<0.01 versus baseline).
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No significant correlation could be found between the changes in blood
pressure and in LVMI (Table 5) for either
valsartan or atenolol treatment.
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Discussion |
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The prevalence of LVH has recently been estimated to be 62% in essential hypertensive patients with a sitting diastolic blood pressure between 100 and 115 mm Hg,25 which is in accordance with our screening results. In contrast to 3 previous studies in patients with LVH26 27 28 who were given the Ang II antagonist losartan, we observed a significant reduction in left ventricular mass after 8 months of treatment with the Ang II antagonist valsartan. As in our study, Cheung26 included only previously untreated patients, but as in the investigation by Himmelmann et al,27 treatment duration was only 12 weeks. However, the most marked effect on LVMI, and especially the difference versus atenolol, occurred between 3 and 8 months of treatment with valsartan. Baseline values of LVMI were comparable between our study and these 2 studies; however, in the long-term (29-month) study reported by Himmelmann and coworkers,28 patients were pretreated and had a normal baseline LVMI of 97 g/m2. One should consider that in the other investigations,26 27 28 the number of patients enrolled ranged between 12 and 24 patients.
The overall extent of reduction in LVMI observed in our trial is comparable to that of other studies.5 6 In a comparative trial between the ACE inhibitor ramipril and atenolol,29 6 months of treatment with atenolol induced only a minor regression of LVMI, from 139 to 133 g/m2; in contrast, ramipril produced a significant reduction, from 136 to 117 g/m2. The reduction of 19 g/m2 obtained with the ACE inhibitor appears to be comparable to our results with an AT1 antagonist.
We found no significant correlation between blood pressure reduction and decrease in left ventricular mass, possibly because of the sample size and the large variability of findings. However, there was a trend for a positive correlation for valsartan, but not for atenolol. In 206 essential hypertensive patients receiving lisinopril and additional HCTZ, no correlation could be demonstrated between change in clinic sitting blood pressure and change in LVMI, whereas a close correlation was found between decrease in average 24-hour ambulatory blood pressure values and reduction in LVMI.30
In renovascular hypertensive rats, Zierhut et al15 observed a significant decrease of LVMI after 12 weeks of treatment with valsartan, comparable to the effect induced by an ACE inhibitor. Treatment with the Ang II antagonist TCV-116 prevented the development of LVH in the spontaneously hypertensive rat model by reducing left ventricular wall thickness and weight and also interstitial fibrosis.31
It has been suggested that AT1 antagonists, like ACE inhibitors, possess a pharmacological effect beyond blood pressure reduction,14 in which blockade of the AT1 receptor may lead to an attenuation of the growth-promoting actions of Ang II.
However, little is known about the presence and role of the AT2 receptor subtype (and other subtypes) in patients with LVH.32 Liu and coworkers33 showed, in rats after myocardial infarction, that a considerable share of the beneficial effects of an Ang II AT1 receptor antagonist could be attenuated by additional treatment with an AT2 antagonist. These findings indicate that stimulation of the AT2 receptor plays an important role in the mechanism of action of selective AT1 receptor antagonists. Irrespective of the mechanism of action, the ELITE trial34 demonstrated that the Ang II antagonist losartan is at least as effective as an ACE inhibitor with regard to prevention of heart failure–related hospital admissions and reduction of total mortality.
Some aspects of our study may be considered to be shortcomings. First, treatment duration was restricted to 8 months. Liebson and coworkers8 described an additional decrease of left ventricular mass after 12 months of treatment with different antihypertensive drug classes.
The addition of HCTZ was required equally in both our treatment groups, and a beneficial influence of this diuretic on LVMI cannot be ruled out. According to Liebson et al8 and others,5 7 the major influence of a diuretic was confined predominantly to the left ventricular internal diameters rather than wall thickness parameters. We did not observe a decrease of left ventricular internal diameters or left ventricular volumes.
The method of measuring LVMI by echocardiography requires some comment. The reproducibility of 2-dimensional and M-mode echocardiography has been validated in our echocardiography laboratory, and variability24 is in accordance with recently published data on the quality of echocardiographic readings.35 36
Confirming experimental data, a considerable regression of LVH was obtained after 8 months of treatment with the Ang II antagonist valsartan in essential hypertensive patients, indicating that valsartan may safely be given to patients with LVH. The long-term clinical benefit of the LVH reduction obtained after chronic treatment with Ang II antagonists has to be elucidated in clinical studies using end points such as cardiovascular events and mortality.37
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Participating General Practitioners
K. Albrecht, S. Mörchen (Undenheim); E. Bakker (Gründau); F. Criveanu (Frankfurt); A. Faust (Mainz); F. Frohnapfel (Ludwigshafen); G. Härter, V. Rudie (Reilingen); V. Janekovic (Frankfurt); E. Reichwein (Villmar); R. Santo (Lahnau); A. Schmidt (Offenbach); R. Schneider (Wetzlar); M. Stoll, A. Dietz (Dreieich); R. Will (Frankfurt); W. Oldenburg (Frankfurt), Germany.
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Acknowledgments |
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We thank Florence Botteri, PhD, Novartis Pharma AG, Switzerland, for her advice and Doris Bach, PhD, Novartis Pharma AG, Switzerland, for statistical evaluations.
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Footnotes |
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Reprint requests to Prof Dr med Petra A. Thürmann, Philipp Klee-Institute of Clinical Pharmacology, Klinikum Wuppertal GmbH, Arrenberger Straße 20, 42117 Wuppertal, Germany.
Received April 13, 1998; revision received June 19, 1998; accepted June 25, 1998.
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G. Nickenig, J. Ostergren, and H. Struijker-Boudier Clinical Evidence for the Cardiovascular Benefits of Angiotensin Receptor Blockers Journal of Renin-Angiotensin-Aldosterone System, March 1, 2006; 7(1_suppl): S1 - S7. [Abstract] [PDF]
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M. P. Schneider, A. U. Klingbeil, C. Delles, M. Ludwig, R. E. Kolloch, M. Krekler, K. O. Stumpe, and R. E. Schmieder Effect of Irbesartan Versus Atenolol on Left Ventricular Mass and Voltage: Results of the CardioVascular Irbesartan Project Hypertension, July 1, 2004; 44(1): 61 - 66. [Abstract] [Full Text] [PDF]
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G. B. J. Mancini, B. Dahlof, and J. Diez Surrogate Markers for Cardiovascular Disease: Structural Markers Circulation, June 29, 2004; 109(25_suppl_1): IV-22 - IV-30. [Full Text] [PDF]
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B. L. Metcalfe, M. J. Huentelman, L. D. Parilak, D. G. Taylor, M. J. Katovich, H. J. Knot, C. Sumners, and M. K. Raizada Prevention of Cardiac Hypertrophy by Angiotensin II Type-2 Receptor Gene Transfer Hypertension, June 1, 2004; 43(6): 1233 - 1238. [Abstract] [Full Text] [PDF]
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 S. Nodari, M. Metra, and L. D. Cas {beta}-Blocker treatment of patients with diastolic heart failure and arterial hypertension. A prospective, randomized, comparison of the long-term effects of atenolol vs. nebivolol Eur J Heart Fail, October 1, 2003; 5(5): 621 - 627. [Abstract] [Full Text] [PDF]
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 N C Sundgren, G D Giraud, P J S Stork, J G Maylie, and K L Thornburg Angiotensin II stimulates hyperplasia but not hypertrophy in immature ovine cardiomyocytes J. Physiol., May 1, 2003; 548(3): 881 - 891. [Abstract] [Full Text] [PDF]
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 W. G. Thomas, Y. Brandenburger, D. J. Autelitano, T. Pham, H. Qian, and R. D. Hannan Adenoviral-Directed Expression of the Type 1A Angiotensin Receptor Promotes Cardiomyocyte Hypertrophy via Transactivation of the Epidermal Growth Factor Receptor Circ. Res., February 8, 2002; 90(2): 135 - 142. [Abstract] [Full Text] [PDF]
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L. Sironi, A. M. Calvio, L. Arnaboldi, A. Corsini, A. Parolari, M. de Gasparo, E. Tremoli, and L. Mussoni Effect of Valsartan on Angiotensin II-Induced Plasminogen Activator Inhibitor-1 Biosynthesis in Arterial Smooth Muscle Cells Hypertension, March 1, 2001; 37(3): 961 - 966. [Abstract] [Full Text] [PDF]
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M. Burnier Angiotensin II Type 1 Receptor Blockers Circulation, February 13, 2001; 103(6): 904 - 912. [Full Text] [PDF]
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M. Schafer, K. Ponicke, I. Heinroth-Hoffmann, O.-E. Brodde, H. M. Piper, and K.-D. Schluter Beta-adrenoceptor stimulation attenuates the hypertrophic effect of alpha-adrenoceptor stimulation in adult rat ventricular cardiomyocytes J. Am. Coll. Cardiol., January 1, 2001; 37(1): 300 - 307. [Abstract] [Full Text] [PDF]
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 R. Rocha, C. T. Stier Jr., I. Kifor, M. R. Ochoa-Maya, H. G. Rennke, G. H. Williams, and G. K. Adler Aldosterone: A Mediator of Myocardial Necrosis and Renal Arteriopathy Endocrinology, October 1, 2000; 141(10): 3871 - 3878. [Abstract] [Full Text] [PDF]
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 M. de Gasparo, K. J. Catt, T. Inagami, J. W. Wright, and Th. Unger International Union of Pharmacology. XXIII. The Angiotensin II Receptors Pharmacol. Rev., September 1, 2000; 52(3): 415 - 472. [Abstract] [Full Text] [PDF]
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 E. Grossman, F. H. Messerli, and J. M. Neutel Angiotensin II Receptor Blockers: Equal or Preferred Substitutes for ACE Inhibitors? Arch Intern Med, July 10, 2000; 160(13): 1905 - 1911. [Full Text] [PDF]
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B. Dahlof Valsartan and the renin-angiotensin-aldosterone system: blood pressure control and beyond Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2_suppl): S14 - S16. [Abstract] [PDF]
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G. T McInnes Saving lives: long-term morbidity and mortality trials with selective angiotensin receptor blocker therapy Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2_suppl): S17 - S20. [Abstract] [PDF]
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A. Zanchetti Cardiac, renal and vascular complications in the diabetic patient Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2_suppl): S21 - S24. [Abstract] [PDF]
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E. L. Schiffrin, J. B. Park, H. D. Intengan, and R. M. Touyz Correction of Arterial Structure and Endothelial Dysfunction in Human Essential Hypertension by the Angiotensin Receptor Antagonist Losartan Circulation, April 11, 2000; 101(14): 1653 - 1659. [Abstract] [Full Text] [PDF]
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N. K Hollenberg and P. S Sever The past, present and future of hypertension management: a potential role for AT1-receptor antagonists Journal of Renin-Angiotensin-Aldosterone System, March 1, 2000; 1(1): 5 - 10. [Abstract] [PDF]
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 P. Paradis, N. Dali-Youcef, F. W. Paradis, G. Thibault, and M. Nemer Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling PNAS, January 18, 2000; 97(2): 931 - 936. [Abstract] [Full Text] [PDF]
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J. S. Gottdiener, P. A. Thurmann, P. Kenedi, A. Schmidt, S. Harder, and N. Rietbrock Influence of the Angiotensin II Antagonist Valsartan on Left Ventricular Hypertrophy in Patients With Essential Hypertension • Response Circulation, August 10, 1999; 100(6): 685 - 688. [Full Text] [PDF]
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B. Pitt Regression of Left Ventricular Hypertrophy in Patients With Hypertension : Blockade of the Renin-Angiotensin-Aldosterone System Circulation, November 10, 1998; 98(19): 1987 - 1989. [Full Text] [PDF]
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W. G. Thomas, Y. Brandenburger, D. J. Autelitano, T. Pham, H. Qian, and R. D. Hannan Adenoviral-Directed Expression of the Type 1A Angiotensin Receptor Promotes Cardiomyocyte Hypertrophy via Transactivation of the Epidermal Growth Factor Receptor Circ. Res., February 8, 2002; 90(2): 135 - 142. [Abstract] [Full Text] [PDF]
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