Influence of the Angiotensin II Antagonist Valsartan on Left Ventricular Hypertrophy in Patients With Essential Hypertension
To the Editor:
The recent article by Thürmann et al1 is of substantial interest in documenting efficacy of a relatively new angiotensin II antagonist for reduction of left ventricular mass in hypertensive patients. However, some features of the study cast doubts on the validity of the results. Moreover, misstatements of fact concerning existing literature further impair the interpretation of these data.
Although the authors report the efficacy of valsartan for regression of left ventricular hypertrophy (LVH), in fact, only the mean reduction of left ventricular (LV) mass is reported rather than the number of individuals with LVH who had sufficient reductions of LV mass to revert to normal. More importantly, despite the emphasis on the efficacy of valsartan, the investigators’ data indicate that LV mass was reduced with atenolol as well. It is unclear whether the reduction of LV mass with atenolol was significantly less than that with valsartan. It can be questioned whether the ≈10 g average difference in LV mass reduction between valsartan- and atenolol-treated patients is biologically or even statistically meaningful. Additionally, there appeared to be equivalent reduction of LV wall thickness with atenolol and with valsartan.
More importantly, the study was not a comparison of single-drug therapy. A third of the patients in both groups received hydrochlorothiazide to achieve hypertension control. Other patients received pretreatment with diuretics, which was considered acceptable because the investigators believed that the effects of diuretics on LV mass and wall thickness have been shown to be negligible. In fact, single-drug comparative studies, including some of those quoted by the authors, have shown substantial efficacy of diuretics for reduction of LV mass, wall thickness, and cavity size.2 3 4 5 It would have been useful to analyze the data with adjustment for the use of hydrochlorothiazide or to have performed a subgroup analysis of patients who did not receive a diuretic. In the present study, hydrochlorothiazide may have accounted for LV mass reduction by its individual action or by acting synergistically with either or both of the 2 study drugs.
Comparative trials of antihypertensive therapy for reduction of LV mass need to include single-drug comparisons of sufficient duration. Assumptions of lack of efficacy of diuretic therapy for LV mass and wall thickness are not supported by the results of recent trials. When patients require medications to control blood pressure other than those described in the hypothesis of the study, intention-to-treat analyses of LV mass reduction are likely to show the effects of the intention rather than the treatment. Neither efficacy of valsartan nor its superiority to atenolol for reduction of LV mass is proven by the present study.
- Copyright © 1999 by American Heart Association
Thürmann PA, Kenedi P, Schmidt A, Harder S, Reitbrock N. Influence of the angiotensin II antagonist valsartan on left ventricular hypertrophy in patients with essential hypertension. Circulation. 1998;98:2037–2042.
Gottdiener JS, Reda DJ, Massie BM, Masterson BJ, Williams DW, Anderson RJ. Effect of single-dose therapy on reduction of left ventricular mass in mild to moderate hypertension: comparison of six antihypertensive agents: the Department of Veterans Affairs Comparative Study Group on Antihypertensive Agents. Circulation. 1997;95:2007–2014.
In reply to the comments of Dr Gottdiener, we want to emphasize that the main objective of our trial was the evaluation of the effect of the angiotensin (AT1)-receptor antagonist valsartan on left ventricular hypertrophy (LVH).R1 A control group was chosen for reasons of trial design and blinding.R2
A reduction of left ventricular mass index (LVMI) of ≥10% or normalization (<134 g/m2 in men and <110 g/m2 in women) occurred in 72% of patients in the valsartan group and in 68.2% in the atenolol group, indicating no difference in this regard. The 90% CI for the reduction of LVMI comparing valsartan with atenolol was stated as 0.85 to 0.97; R=0.91. This was not statistically significant. Posterior and end-diastolic wall thicknesses were reduced by 1.2 and 1.5 mm (each P<0.0001), respectively, after valsartan and by 0.8 and 1.0 mm, respectively, after atenolol (P<0.005 and P<0.0001), showing a marginal difference between treatments.
Nineteen percent of patients in the intent-to-treat population had prior exposure to antihypertensive therapy (for <4 weeks), and 1 patient in each treatment group had received a diuretic during the 12 months before the trial.
Antihypertensive monotherapy may not be sufficient in most patients with end-organ damage. Therefore, about one third of our study population required additional medication to ensure adequate blood pressure control. Addition of hydrochlorothiazide (HCTZ) was required to the same degree in both groups and was therefore of comparable benefit in both treatment groups. It remains unproven whether combination treatment with an AT1-receptor antagonist and a diuretic exerts a significantly higher pharmacological synergy than the combination of atenolol and HCTZ. Therefore, a statistical analysis excluding patients with diuretic cotreatment was not performed.
The effect of diuretics on left ventricular mass cannot be neglected, according to recent trials.R3 However, a number of comparative trials, also with an AT1-antagonist,R4 and a meta-analysisR5 clearly demonstrated the superiority of drugs that block the effects of angiotensin II over the effects of diuretics. However, we do agree that more and larger studies have to be performed to assess the efficacy of AT1-antagonists in terms of LVH regression.
Thürmann PA, Kenedi P, Schmidt A, Harder S, Rietbrock N. Influence of the angiotensin II antagonist valsartan on left ventricular hypertrophy in patients with essential hypertension. Circulation. 1998;98:2037–2042.
Gottdiener JS, Reda DJ, Massie BM, Materson BJ, Williams DW, Anderson RJ. Effect of single-drug therapy on reduction of left ventricular mass in mild to moderate hypertension: comparison of six antihypertensive agents: the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Circulation. 1997;95:2007–2014.