(Circulation. 1998;98:1350-1353.)
© 1998 American Heart Association, Inc.
Effect of Age Adjustment in Predicting Outcome
Renée B.A. van den Brink, MD;
Egbart Dekker, MD;
; Hans A. Verheul, MD
Department of Cardiology,
Academic Medical Center,
Amsterdam, The Netherlands
Jan G.P. Tijssen, PhD
Department of Clinical Epidemiology and
Biostatistics Academic Medical Center,
Amsterdam, The Netherlands
To the Editor:
We read with interest the report of Ling et al1
that examined long-term outcome in a cohort of patients in whom pure
mitral regurgitation due to flail leaflet was first
diagnosed by echocardiography between 1980 and
1989.
In the introduction, the authors correctly state that it is uncertain
whether early surgery or conservative management should be the
preferred approach in these patients, irrespective of symptoms.
Accordingly, they analyzed their cohort on an
"intention-to-treat" basis, comparing follow-up events among
patients who underwent surgery within 1 month after the diagnosis (the
early-surgery group) with those who did not (the conservative-treatment
group). Because this was not a randomized trial, the validity of the
study is threatened by incomparability of prognosis of both treatment
groups at baseline (ie, confounding).
Age is always an extremely important potential confounder. When
the baseline characteristics of the patients at the time of diagnosis
are compared (Table 1 in the article), there is an important difference
in mean age between the early-surgery group and the
conservative-treatment group (61.1 versus 66.5 years), which is called
"slight" by the authors. The estimated probability of 10-year
survival for 61- and 67-year-old men (at approximately 1990 in The
Netherlands) was 77.7% and 63.7% respectively, a difference of 14%.
The same difference (14% in 10-year survival) was found between early
surgery and conservative treatment in the present study. The
horizontal distance between the 2 groups in Figure 1 in the article is
4 years; this means that patients in the early-surgery group lived
4 years longer. If we look again at the Dutch general population in
1990, 61-year-olds lived 4 years longer than 67-year-olds. Thus, the
expected impact of the age factor alone is of the same magnitude as the
survival difference presented here as a result of treatment. It
is unlikely that all age-related confounding is eliminated by including
age as a linear covariate in a multivariate Cox model,
if the data originate from an elderly population followed up over a
long period of time. After all, the use of a linear component in the
Cox model fails to correct for the extremely nonlinear (almost
exponential) increase of "background mortality" (ie, the expected
mortality in the source population) in higher-age groups. Thus, the
baseline characteristic of age was biased in favor of survival in the
early-surgery group, and it is doubtful whether this bias has been
sufficiently removed.
Although there are more effective ways to deal with differences
in age and associated expected mortality between 2 groups of
patients,2 we agree with the authors that the
only way to solve the issue of timing of surgery in
asymptomatic patients with pure mitral
regurgitation due to flail leaflets and no signs of
left ventricular dysfunction is to perform a randomized,
controlled trial.
References
1.
Ling LH, Enriquez-Sarano M, Seward JB, Orszulak TA,
Schaff HV, Bailey KR, Tajik AJ, Frye RL. Early surgery in patients with
mitral regurgitation due to flail leaflets: a long-term
outcome study. Circulation. 1997;96:1819–1825.[Abstract/Free Full Text]
2.
Verheul HA, van den Brink RBA, Bouma BJ, Hoedemaker G,
Moulijn AC, Dekker E, Bossuyt P, Dunning AJ. Analysis of risk
factors for excess mortality after aortic valve replacement.
J Am Coll Cardiol. 1995;26:1280–1286.[Abstract]
Response
Maurice Enriquez-Sarano, MD
Divisions of Cardiovascular Diseases and Internal Medicine
Kent R. Bailey, PhD
Department of Health Sciences Research Mayo Clinic and Mayo
Foundation,
Rochester, Minn
We appreciate the interest of R.B.A. van den Brink et al in our
recent publication on early surgery in patients with mitral
regurgitation due to flail
leaflets.1 They raise an important question
regarding the adequacy of our age adjustment and point to expected
survival data relative to a 5-year age difference, suggesting that our
"linear" age term in the Cox model does not adequately account for
the increasing mortality at older ages. Several points need to be made
in response to this concern:
First, it is not at all clear how relevant expected survival data for
entire living populations are to the question of how to adjust survival
data for a specific disease. Although comparison with expected survival
data is useful for large populations, in particular of young patients,
it is more difficult to interpret in older patients for several
reasons.
The symptoms in the general "elderly" population of comparison are
unknown, but it is a common observation that a notable percentage of
this population expresses limitation in exercise capacity. Physical
activity and exercise capacity are associated with long-term
mortality,2 so that the exact expected survival
of patients may vary according to their symptoms. Therefore, it is
possible that the expected survival of mostly asymptomatic
and elderly patients, such as those in the conservative treatment
group, may well be far better than the "standard" expected
survival.
Comorbidity is an important determinant of
survival3 but is indeterminable in the general
population. Comorbidity increases with age but cannot be adjusted for
in the comparison to expected survival. Indeed, a population with
comorbidity lower than the general population may have an expected
survival that is better than "standard." Conversely, the results of
our study held true after adjustment in multivariate
analysis for comorbidity.
The subset of 50-year-olds who have a disease may be a very different
subset from the subset of 70-year olds who have the same disease.
Indeed, if we had large enough populations of patients with a disease
and without surgical intervention, we would almost certainly want to
use these populations as the reference populations for calculating the
appropriate age adjustments. Thus, internal age adjustment is not to be
lightly dismissed in favor of the use of general external
populations.
Second, the point may have been missed that, although age was biased in
favor of the early-surgery group, the very important prognostic factor
of symptoms was weighted against the early-surgery group. Because we
appropriately controlled for age but also for the baseline predictors
of outcome,4 a very sizable narrowing due to age
adjustment was strongly counteracted by the adjustment for these
predictors of outcome.
Third, it is incorrect to say that the proportional hazards model with
a linear age term makes a linear adjustment for age. Despite the term
"linear," age enters into the Cox model in an exponential way. In
our fitted model, every year of age was associated with a
multiplicative factor of 1.1 in the hazard function. This factor is
compounded, so that at a 5.4-year age difference, the factor is 1.67,
or 67% higher, and at 10 years, it is 2.8, ie, a 3-fold higher risk.
If we apply the 2 modes of correction (Cox model and expected survival
based on the 1980 US white population) to the early-surgery group, a
5.4-year age difference decreases the expected 10-year survival from
79% to 67% using our Cox model and to 65% using the expected
survival, demonstrating the magnitude of the age adjustment used in our
model and the fact that these 2 modes of correction produce very
similar results. Therefore, the association of outcome with treatment
strategy cannot be attributed to our approach to age adjustment.
van den Brink et al correctly echo our statement that only a randomized
trial can give a completely reliable answer to the question of the
impact of early surgery on the outcome of severe mitral
regurgitation. However, we believe that the results of
our observational study suggest strongly that early surgery provides an
improved outcome, and these results represent a first step in
the consideration of this option for patients with severe mitral
regurgitation. The considerable recent improvements in
surgical results5 6 7 make this option clinically
viable until a randomized trial is completed.
References
1.
Ling LH, Enriquez-Sarano M, Seward JB, Orszulak
TA, Schaff HV, Bailey KR, Tajik AJ, Frye RL. Early surgery in patients
with mitral regurgitation due to flail leaflets: a
long-term outcome study. Circulation. 1997;96:1819–1825.
2.
Kampert J, Blair S, Barlow C, Kohl H. Physical
activity, physical fitness and all-cause and cancer mortality: a
prospective study of men and women. Ann Epidemiol. 1996;6:452–457.[Medline]
[Order article via Infotrieve]
3.
Charlson M, Pompei P, Ales K, MacKenzie C. A new
method of classifying prognostic comorbidity in longitudinal studies:
development and validation. J Chronic Dis. 1987;40:373–383.[Medline]
[Order article via Infotrieve]
4.
Ling LH, Enriquez-Sarano M, Seward JB, Tajik AJ,
Schaff HV, Bailey KR, Frye RL. Clinical outcome of mitral
regurgitation due to flail leaflet. N Engl
J Med. 1996;335:1417–1423.[Abstract/Free Full Text]
5.
Enriquez-Sarano M, Tajik A, Schaff H, Orszulak T,
Bailey K, Frye R. Echocardiographic prediction of
survival after surgical correction of organic mitral
regurgitation. Circulation. 1994;90:830–837.[Abstract/Free Full Text]
6.
Enriquez-Sarano M, Schaff H, Orszulak T, Tajik A,
Bailey K, Frye R. Valve repair improves the outcome of surgery for
mitral regurgitation. Circulation. 1995;91:1264–1265.[Free Full Text]
7.
Cohn L, Couper G, Kinchla N, Collins JJ. Decreased
operative risk of surgical treatment of mitral
regurgitation with or without coronary artery
disease. J Am Coll Cardiol. 1990;16:1575–1578.[Abstract]
