(Circulation. 1997;95:1983-1985.)
© 1997 American Heart Association, Inc.
Articles |
Do Antihypertensive Drugs Differ in Their Ability to Regress Left Ventricular Hypertrophy?
From the Department of Medicine, The New York Hospital-Cornell Medical Center, New York, NY.
Correspondence to Richard B. Devereux, MD, Division of Cardiology, Box 222, The New York Hospital–Cornell Medical Center, 525 E 68th St, New York, NY, 10021. E-mail rbdevere{at}mail.med.cornell.edu
Key Words: Editorials • echocardiography • hypertrophy • hypertension
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Introduction |
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 Top Introduction Criteria for an Optimal...What Have Previous Studies...How Does the Veterans...What Do We Still...References |
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Numerous studies have documented a strong relationship between left ventricular (LV) hypertrophy and the risk of cardiovascular events in hypertensive patients.1 2 3 4 5 6 Furthermore, initial evidence suggests that whether LV hypertrophy is reduced or progresses over time directly influences the risk of subsequent complications.7 8 9 10 In this context, it is understandable that considerable attention has been devoted to determining whether different forms of antihypertensive therapy differ with regard to their ability to induce regression of hypertensive LV hypertrophy. Some progress has been made, but important questions remain unanswered after the recent appearance of a meta-analysis of randomized double-blind studies of LV hypertrophy regression11 as well as detailed analyses of echocardiographic data from the Treatment of Mild Hypertension Study (TOMHS) and other large trials12 13 and, in this issue of Circulation, from the long-awaited Veterans Administration study of single-drug antihypertensive treatment.14 To place this recent evidence in context, it is useful to consider the characteristics of optimal study designs for trials of LV hypertrophy regression that help make their results conclusive and generalizable.
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Criteria for an Optimal Study of LV Hypertrophy Regression |
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TopIntroductionCriteria for an Optimal...What Have Previous Studies...How Does the Veterans...What Do We Still...References |
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To add useful information to the existing large but flawed literature, studies of LV hypertrophy regression should at least be randomized and double-blind and use an anatomically validated method of measuring LV mass to compare an active agent with either a placebo or one or more other active agents over
6 months in
hypertensive women and men, many or all of whom have LV
hypertrophy at baseline.15 Relatively small
studies of this type, with 20 to 30 patients per treatment arm, may be
used to address specific pathophysiological issues
in detail or to explore the effects of new therapeutic agents, but they
cannot provide conclusive comparisons between drugs. To test
definitively whether different classes of antihypertensive agents have
contrasting effects on hypertensive LV hypertrophy, studies
need to enroll as many as 150 to 200 patients per treatment arm and
last at least 1 year. Studies of this magnitude may have implications
for the treatment of hypertension worldwide; thus, it is important that
they be conducted in ethnically diverse populations because of evidence
that the pathophysiology of hypertension may differ between whites and
blacks and perhaps other ethnic groups. Even larger studies, with 500
to 600 patients per treatment arm and study durations of 4 years,
are needed to have good power to determine whether treatment-induced
changes in LV mass or in other measures of preclinical
cardiovascular disease such as carotid artery wall
thickness or atheroma predict subsequent
cardiovascular events well enough to serve as
surrogates for morbid events in subsequent treatment
trials.10 |
What Have Previous Studies Shown? |
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TopIntroductionCriteria for an Optimal...What Have Previous Studies...How Does the Veterans...What Do We Still...References |
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In the early 1980s, wide publicity was given to the assertion by leading investigators that diuretics, drugs that have played an important role in reducing the complications of hypertension, had little if any ability to regress hypertensive LV hypertrophy,16 despite some early evidence to the contrary.17 This contention has now been conclusively disproved by findings from the TOMHS study12 and by the results of a meta-analysis by Schmieder et al11 of well-designed small studies. In analyses that adjusted for differences among treatment groups in study duration, Schmieder et al11 found that the 258 patients treated with diuretics had 6.8% greater reduction of LV mass than the 189 patients in 13 placebo-treated groups. The TOMHS used a complex study design in which all 819 patients received a nutritional-hygienic intervention designed to reduce weight and sodium and alcohol intake and to increase physical exercise. The group of patients who received placebo pills had, on average, normalization of blood pressure (to a mean of 131/82 mm Hg) and of LV mass (to a mean of 178 g). Nearly three quarters of TOMHS participants were randomized to receive additional small doses of one of five antihypertensive drugs. The patients who received chlorthalidone, a diuretic, had the greatest reduction in LV mass during treatment but also the highest pretreatment LV mass, raising the possibility that they were the only group with any residual LV hypertrophy on which a drug could act after the impressive effects of the nutritional-hygienic regimen.
In contrast to the clear refutation provided by recent data of the concept that diuretics are without effect on LV hypertrophy, the even more important question of whether one or another type of agent is more effective in this regard has not been resolved. The meta-analysis by Schmieder et al11 suggested that ACE inhibitors have the greatest ability to reduce LV mass, with somewhat lesser effects for, in descending order, calcium channel blockers, diuretics, and ß-adrenergic receptor blockers. However, a meta-analysis by Fagard18 suggested equal efficacy of ACE inhibitors and calcium blockers. A relatively large therapeutic trial by Agabiti-Rosei et al13 supported the concept that ß-blockers might have somewhat less effect than other agents on LV mass, but it was conducted in a study population that did not include nonwhite patients and was too small (total n=111) to yield definitive results.
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How Does the Veterans Administration Study Improve Our Knowledge? |
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TopIntroductionCriteria for an Optimal...What Have Previous Studies...How Does the Veterans...What Do We Still...References |
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The study presented by Gottdiener et al14 in this issue of Circulation is the first to compare the effects on echocardiographic LV mass of single-agent antihypertensive therapy in a large group (n=587 at baseline, 58% black) of patients with definite hypertension (mean baseline pressure, 153/100 mm Hg) and a high prevalence (45%) of LV hypertrophy at study entry. Echocardiograms were performed by standard methods, repeated after both short and longer durations of treatment (8 weeks and 1 year) and read blindly in a central laboratory that has extensive experience with this skill-dependent technique. Additional attractive features of the trial are its use of monotherapy and selection of a prototypic agent in each of six drug classes (diuretic, ß-blocker, ACE inhibitor, calcium channel blocker,
-adrenergic receptor
blocker, and centrally acting sympatholytic agents).
Two of the principal results of the present study add to
present knowledge of LV hypertrophy regression. First,
short-term therapy over only 8 weeks had no significant effects on LV
mass in any of the treatment groups, and the weak trends that existed
toward greater LV mass reductions in the groups treated with diltiazem
and clonidine were not confirmed by results obtained after 1 year of
treatment. Second, after 1 year of treatment, the greatest reductions
in LV mass were obtained by captopril (-15 g, P=.05) and
hydrochlorothiazide (-14 g, P=.08), a
minimal reduction (-4 g, P=NS) by atenolol, and no change
or insignificant increases in LV mass (from -0.5 g to +7 g, all
P=NS) by clonidine, prazosin, and diltiazem. In further
analyses that took changes in covariates into account, the
decrease over time in LV mass in the diuretic-treated and ACE
inhibitor–treated groups were statistically greater than
those in the groups treated with the calcium blocker, -adrenergic
receptor blocker, and central sympatholytic agent. These findings make
an interesting parallel with the known prognostic benefits of treatment
with diuretics and ACE inhibitors, respectively, in
patients with hypertension or with heart failure or recent myocardial
infarction19 20 and the lack of such a proven benefit for
the other three classes of drugs. The intermediate result obtained by
Gottdiener et al14 with a ß-adrenergic receptor blocker
makes an interesting but inconclusive parallel with the British Medical
Research Council trial in which ß-blocker therapy appeared to be less
beneficial than treatment with a diuretic.21
However, several aspects of the Veterans Administration study limit its conclusiveness. Although the inclusion of a substantial number of black patients enhances its representativeness, the lack of women in the study limits its applicability to the majority of older hypertensive patients. Second, by the end of the 1-year follow-up period, only 230, or 39%, of 587 patients with initial echocardiograms and only 27% of patients in whom baseline echocardiograms were attempted remained in the trial. The much lower retention rate than in most therapeutic trials is due in part to the decision—in contrast to clinical practice, in which a second antihypertensive agent is commonly added to achieve pressure control—to drop patients if their pressure was not controlled by a single agent. In addition, there were serious difficulties in obtaining baseline and follow-up echocardiograms in some centers. The high dropout rate left fewer than 40 patients in most treatment arms at the end of 1 year, a number suitable to an initial exploratory study but insufficient to give definitive results. Second, retention rates differed by nearly twofold (15% to 28%) among treatment arms and tended to be higher for patients who at baseline had lower blood pressure and lower sodium intake and were black than for other groups. As an example of how this interacted with the assigned treatments, by the end of 1 year of therapy, the proportion of black patients was statistically lower (P<.05) among those receiving the drugs (captopril and atenolol) most likely to interrupt activity of the renin-angiotensin system than among those receiving agents with least activity against this system. Third, although no ambulatory or home blood pressure recordings were performed, it is possible that once-daily use of hydrochlorothiazide may have achieved better 24-hour blood pressure control than twice-daily doses of the relatively short-acting agents captopril and prazosin or even once-daily use of atenolol, which has been suggested to have a shorter duration of action than commonly recognized.22 Finally, several methodological choices made by the investigators partially limit interpretation of results. These choices include (1) the use of a formula known to overestimate anatomic LV mass by nearly 20%23 ; (2) the use in analyses of "the blood pressure averages for the first two consecutive visits at which goal blood pressure was achieved" instead of blood pressure at the time of the follow-up echocardiograms; and (3) the decision to perform analyses in which LV mass change was adjusted for covariates not in the entire groups of patients assigned to specific treatment arms but rather in subgroups of patients with lower, intermediate, or higher levels of baseline LV mass.
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What Do We Still Need to Learn? |
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TopIntroductionCriteria for an Optimal...What Have Previous Studies...How Does the Veterans...What Do We Still...References |
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If one were to add the data from the Veterans Administration trial14 and those from the medium-sized study reported by Agabiti-Rosei et al13 to the results of the recent meta-analysis by Schmieder et al,11 one might calculate that ACE inhibitors and perhaps diuretics or calcium blockers would be more effective than ß-blockers and several less widely used antihypertensive drug classes for regression of hypertensive LV hypertrophy. However, such retrospective pooling of data must always be suspect because of the need to merge findings from studies that often differ in important ways and because of the likelihood that some relevant but negative studies have gone unreported.24 The only sure way to obtain definitive data on the relative ability of antihypertensive drugs to regress LV hypertrophy is to perform studies comparing the effects of different agents on LV mass in ethnically diverse groups of women and men with established hypertension, many or all of whom have LV hypertrophy, over a treatment period of at least 1 year.15 Fortunately, as we have recently reviewed elsewhere,10 a number of such trials are now ongoing, comparing an ACE inhibitor with a diuretic (LIVE study, Phillipe Gosse, MD, personal communication, 1996) or with a long-acting calcium channel antagonist,25 comparing a calcium channel blocker with a diuretic,26 and comparing an angiotensin receptor blocker with a ß-blocker.27
Finally, the ultimate question with regard to hypertensive LV hypertrophy is not whether one agent or another is somewhat more effective in reversing it but rather whether regression of hypertensive LV hypertrophy confers a prognostic benefit over and above the degree of induced lowering of blood pressure. To answer this question will require studies that are much larger than either the Veterans Administration monotherapy trial14 or the Treatment of Mild Hypertension Study.12 At present, at least one study is under way that is designed to have adequate power to answer this question,27 and improvements in methods for ECG assessment of hypertrophy28 may make it possible to obtain important information in this regard from previous large trials in which findings on serial ECGs could be related to the subsequent occurrence of morbid events.
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Acknowledgments |
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This work was supported in part by grant HL-47540 from the National Heart, Lung, and Blood Institute, Bethesda, Md, and grant CDSP 964-0A from Merck and Co, White Horse Station, NJ.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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