NDT Advance Access originally published online on September 9, 2005
Nephrology Dialysis Transplantation 2005 20(11):2301-2303; doi:10.1093/ndt/gfi092
© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Editorial Comment
Efficacy of antihypertensive treatment: which endpoints should be considered?
Giuseppe Mancia and
Guido Grassi
Clinica Medica, Dipartimento di Medicina Clinica, Prevenzione e Biotecnologie Sanitarie, Università Milano-Bicocca, Centro Auxologico Italiano and Centro Interuniversitario di Fisiologia Clinica e Ipertensione, IRCCS Policlinico, Milano, Italy
Correspondence and offprint requests to: Prof. Giuseppe Mancia, Clinica Medica, Ospedale S. Gerardo dei Tintori, Via Donizetti 106, 20052, Monza, Milan, Italy. Email: giuseppe.mancia{at}unimib.it
Keywords: antihypertensive treatment; cardiovascular mortality
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Introduction
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Knowledge on the benefit of antihypertensive treatment owes
a great deal to antihypertensive drug trials based on incidence
of morbidity and mortality [
1]. These trials have demonstrated
that antihypertensive drugs reduce cardiovascular morbid and
fatal events of hypertensive individuals, counteracting their
increased cardiovascular risk. They also demonstrated that this
reduction occurs in males and females of different ages, ethnicities
and clinical conditions and that thus the protection is virtually
universal across the demographic and pathophysiological spectrum
that characterizes an elevated blood pressure. They have finally
demonstrated that drugs capable of lowering blood pressure protect
hypertensive patients via sizes and designs that exclude even
the remote possibility of ‘chance’ results as well
as of errors due to selection bias, investigators’ and
patients’ expectations, and inappropriate or unbalanced
identification of events.
The above has generated the widespread opinion that information provided by morbidity/mortality trials is the most important one in a hypothetical scale of scientific soundness [2], and the only one on which Guidelines on antihypertensive treatment should be based on. This, however, overlooks the fact that morbidity/mortality trials on antihypertensive treatment are not devoid of limitations and that failure to appreciate them can endanger proper interpretation of available data and make it more difficult to devise studies that allow further progress to be made [3].
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First limitation of clinical trials — selection bias
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One of the limitations of morbidity/mortality trials derives
from the need to ensure, through a stringent selection process,
that the population under study is relatively homogeneous and
compliant to treatment, in order to minimize confounders that
can make interpretation of the data more difficult. This, however,
makes the study population different from that seen in clinical
practice in which the disease addressed by the trial much more
frequently coexists with demographic conditions and morbidities
that make the population much more heterogeneous. Furthermore,
in trials, physicians’ expertise and patients’ motivation
and compliance are in general better than those encountered
in clinical practice, in which therapeutic mistakes and inadequacies
are more common, with an overall outcome that can be worse than
that of patients followed in trials even when no active treatment
is given [
4].
Morbidity/mortality trials, however, have three additional limitations, which may be even more important than the previous one. One limitation is that the trial results show the prevailing effect of the treatment under study without guaranteeing the evidence that it does, on average, more good than harm throughout the recruited population. This is customarily addressed by subgroup analysis of the data (for which the statistical power is often insufficient), but no analysis can exclude the fact that those interventions shown to be beneficial in the overall study population, be they a specific antihypertensive treatment regimen or a target blood pressure value, are harmful to some individuals. Advocates of an indiscriminate and mandatory application of trial results to clinical practice should give this limitation greater consideration.
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Second limitation of clinical trials — ‘intention to treat’ analysis
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A second limitation is that trials include patients who (1)
drop out from prescribed treatment because of side effects,
withdrawal of the initial consensus and/or decision of the investigator,
(2) take the comparison drug(s) in addition to or instead of
the prescribed one(s) and (3) are lost, for a variety of reasons,
to follow-up information. In well-performed hypertension trials,
this last phenomenon can be kept at a minimum, whereas the former
two may involve up to 30–40% and 20–25% of the recruited
population, respectively [
5,
6]. This means a large reduction
in the number of patients under truly different treatment regimens
with a substantial loss of statistical power and a serious bias
(given that the analysis has to be done on an ‘intention
to treat’ basis to ensure full similarity of the comparison
groups at start of treatment) in favour of ‘pseudoequivalence’,
i.e. of lack of differences between treatment regimens. It is
not unrealistic to speculate that this might have played a role
in the almost invariable absence of differences in morbidity
and mortality between different antihypertensive treatments
reported in trials. Indeed, in 15 trials comparing different
antihypertensive drugs, a between-group difference in cardiovascular
morbidity and mortality was seen in only two trials [
2].
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Third limitation of clinical trials — time and age scale
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A third and important limitation concerns the trial time scale.
Because of their cost and organizational complexity, trials
can only last a few years (usually 3 to 5 years), during which
time the number of events has to be high enough to give them
the required statistical power. This means that only individuals
at high cardiovascular risk are suitable candidates for recruitment,
information being thus largely limited to those in whom severe
hypertension, multiple cardiovascular risk factors, diabetes,
a history of cardiovascular or renal diseases or an advanced
age are present. It also means that the benefit of antihypertensive
treatment in lower risk young or middle age individuals is only
inferential. It finally means that evidence is limited to only
a small fraction of the life expectancy (20–30 years)
of many patients. This poses several questions to which morbidity/mortality
trials have not provided an answer. First question: is the benefit
of antihypertensive treatment seen in elderly/high-risk individuals
shared by young/low-risk patients to an extent that makes the
cost/benefit ratio worthwhile? Second question: is the benefit
seen over the few years of trial duration maintained over the
following years? Third question: the conclusion has been reached
by trials that the cardiovascular protection provided by antihypertensive
treatment depends substantially on blood pressure reduction
‘
per se’ (regardless of how it is obtained). Does
this conclusion hold true only for elderly and/or high-risk
individuals in whom the cardiovascular system is already damaged
and the blood pressure reduction possibly the only defence left,
but not in young patients with incipient damage? And finally,
does trial evidence on reduction of cardiovascular morbidity
and mortality in high-risk/elderly patients miss a fundamental
aspect of prevention, i.e. to prevent in young or middle-age
subjects at lower risk the progression towards a high-risk condition?
This last question is of crucial importance because once the
cumulative effect of risk factors favours the progression to
a high-risk state, no treatment can obtain full reversal, the
cardiovascular risk remaining relatively high even when all
interventions of proven benefit are implemented [
7].
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Design of future clinical trials
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The problem of how to effectively obtain evidence addressing
the above issue is of crucial relevance to plan future research
and achieve progress in the cardiovascular prevention area.
Obviously, morbidity/mortality trials are not suited for this
purpose, because this would require an excessive number of young/middle-aged
or otherwise low-risk subjects and a study duration which no
one can afford. A further consideration is that the mechanisms
responsible for the progression of subclinical disease are not
identical to or superimposable upon those triggering clinical
events. What is the best option? In our opinion, trials should
focus on the question whether a given treatment improves total
cardiovascular risk and prevents delays or regresses subclinical
organ damage. Clinical events ultimately depend on the presence
of such subclinical target organ damage, because no event occurs
unless it is preceded by subclinical structural and/or functional
target organ alterations. This is the goal of treatment in young
and middle-aged hypertensive individuals at lower risk. The
rationale to reduce blood pressure is not to prevent an unlikely
event in the subsequent 3 or 4 years, but to prevent the progression
of organ damage which will present as an event many years later.
If one presents evidence of protection based on effects of treatment of risk factors and/or organ damage alone, this is persistently countered by the argument that these endpoints are ‘soft’ or ‘surrogate’, as compared to the ‘hard’ ones provided by morbidity/mortality trials. The opposition also makes use of previous studies in which improvement of the ‘surrogate’ goal was not paralleled by a significant effect on clinical morbid or fatal events which may have even gone in an opposite direction. Past negative experience, however, does not detract from the soundness of the concept that these intermediate endpoints are clinically valid and can provide evidence on a fundamental aspect of prevention which morbidity/mortality trials cannot address. The above-mentioned discrepancies between soft and hard endpoints only underline the fact that the choice of ‘surrogates’ must be a careful one. Only surrogates fitting a number of criteria should be selected and used.
The requirements should be that they are non-invasive and quantifiable in a reproducible fashion without an excessive degree of expertise and time required, so that the results can eventually be transferred to clinical practice. Furthermore, the measures employed should have been clinically validated — which means that the organ dysfunction they show should be associated with and be responsible for a worse outcome — and the outcome should have been shown to improve when the dysfunction is corrected by treatment. Several measures of organ damage have been shown to be of prognostic significance (Table 1), although in a number of instances lack of a standardized approach as well as the sophisticated nature of the technologies and cost involved makes it difficult to adopt them on a large scale, and renders the planning of such trials problematic. Nevertheless, evidence has recently been obtained of an independent association between the improvement of organ damage by treatment and concomitant reduction in the incidence of cardiovascular events. This has been the case for treatment-induced reduction of urinary protein excretion [8,9] and of left ventricular hypertrophy [10–12]. Thus use of these well-validated measures is today acceptable as a marker of cardiovascular protection.
Conflict of interest statement. None declared.
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References
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- 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension. Guidelines Committee. J Hypertens 2003; 21: 1011–1053[CrossRef][Web of Science][Medline]
- Swales JD. Clinical trials: what more is needed? A critical view. J Hypertens 1996; 14 [Suppl]: S83–S86
- Mancia G. Role of large clinical trials in providing information on antihypertensive treatment. Importance and limitations. J Hypertens 2005; in press.
- Wilcox RG, Hampton JR, Banks DC et al. Trial of early nifedipine in acute myocardial infarction: the Trent study. Br Med J 1986; 293: 1204–1208[Abstract/Free Full Text]
- Medical Research Council Working Party. MRC Trial of treatment of mild hypertension: principal results. Medical Research Council. Br Med J 1985; 291: 97–104[Abstract/Free Full Text]
- ALLHAT Officers and Coordinators for the ALLHAT Collaborative Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to Angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: The Antihypertensive Lipid-Lowering Treatment to prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: 2981–2997[Abstract/Free Full Text]
- Hypertension Detection and Follow-up Program Cooperative Group. Five-year findings of the hypertension detection and follow-up program I. Reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA 1979; 242: 2562–2571[Abstract/Free Full Text]
- de Zeeuw D, Remuzzi G, Parving HH et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 2004; 110: 921–927[Abstract/Free Full Text]
- Ibsen H, Olsen MH, Wachtell K et al. Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study. Hypertension 2005; 45: 198–202[Abstract/Free Full Text]
- Mathew J, Sleight P, Lonn E et al. for the Heart Outcomes Prevention Evaluation (HOPE) Investigators. Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril. Circulation 2001; 104: 1615–1621[Abstract/Free Full Text]
- Devereux RB, Wachtell K, Gerdts E et al. Prognostic significance of left ventricular mass change during treatment of hypertension. JAMA 2004; 292: 2350–2356[Abstract/Free Full Text]
- Verdecchia P, Angeli F, Borgioni C et al. Changes in cardiovascular risk by reduction of left ventricular mass in hypertension: a meta-analysis. Am J Hypertens 2003; 16: 895–899[CrossRef][Web of Science][Medline]
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Introduction
First limitation of clinical...