Context Microalbuminuria is a risk factor for cardiovascular (CV) events. The
relationship between the degree of albuminuria and CV risk is unclear.
Objectives To estimate the risk of CV events in high-risk individuals with diabetes
mellitus (DM) and without DM who have microalbuminuria and to determine whether
levels of albuminuria below the microalbuminuria threshold increase CV risk.
Design The Heart Outcomes Prevention Evaluation study, a cohort study conducted
between 1994 and 1999 with a median 4.5 years of follow-up.
Setting Community and academic practices in North and South America and Europe.
Participants Individuals aged 55 years or more with a history of CV disease (n =
5545) or DM and at least 1 CV risk factor (n = 3498) and a baseline urine
albumin/creatinine ratio (ACR) measurement.
Main Outcome Measures Cardiovascular events (myocardial infarction, stroke, or CV death);
all-cause death; and hospitalization for congestive heart failure.
Results Microalbuminuria was detected in 1140 (32.6%) of those with DM and 823
(14.8%) of those without DM at baseline. Microalbuminuria increased the adjusted
relative risk (RR) of major CV events (RR, 1.83; 95% confidence interval [CI],
1.64-2.05), all-cause death (RR, 2.09; 95% CI, 1.84-2.38), and hospitalization
for congestive heart failure (RR, 3.23; 95% CI, 2.54-4.10). Similar RRs were
seen for participants with or without DM, even after adjusting for other CV
risk factors (eg, the adjusted RR of the primary aggregate end point was 1.97
[95% CI, 1.68-2.31] in those with DM and 1.61 [95% CI, 1.36-1.90] in those
without DM).Compared with the lowest quartile of ACR (<0.22 mg/mmol), the
RRs of the primary aggregate end point in the second quartile (ie, ACR range,
0.22-0.57 mg/mmol) was 1.11 (95% CI, 0.95-1.30); third quartile, 1.38 (95%
CI, 1.19-1.60; ACR range, 0.58-1.62 mg/mmol); and fourth quartile, 1.97 (95%
CI, 1.73-2.25; ACR range, >1.62 mg/mmol) (P for trend
<.001, even after excluding those with microalbuminuria). For every 0.4-mg/mmol
increase in ACR level, the adjusted hazard of major CV events increased by
5.9% (95% CI, 4.9%-7.0%).
Conclusions Our results indicate that any degree of albuminuria is a risk factor
for CV events in individuals with or without DM; the risk increases with the
ACR, starting well below the microalbuminuria cutoff. Screening for albuminuria
identifies people at high risk for CV events.
Diabetes mellitus (DM) is a strong risk factor for cardiovascular (CV)
disease.1 Compared with those who do not have
DM, people with DM have a 2- to 4-fold increased risk of subsequent CV disease.2-4 Risk factors that independently
increase CV risk in people with DM include smoking, hypertension, dyslipidemia,3 renal dysfunction,5
and hyperglycemia.6-10
Recently, data from several studies have established microalbuminuria (MA),
or dipstick-negative albuminuria, as another CV risk factor. Microalbuminuria
is reported in approximately 30% of middle-aged patients with either type
1 or type 2 DM and in approximately 10% to 15% of middle-aged individuals
who do not have DM.11-13
Although MA is associated with other risk factors in those with or without
DM,11,13,14 it is
also an independent predictor of future strokes, death, and myocardial infarction
(MI).15-19
Moreover, MA may also predict future congestive heart failure (CHF). However,
at present, there are few prospective data regarding this association.20-23
Despite being increasingly recognized as a CV risk factor, the definition
of MA was based on its ability to predict diabetic nephropathy (ie, macroalbuminuria
or clinical proteinuria). Whether individuals with albumin excretion rates
below the MA threshold are also at risk for CV disease or whether there is
a progressive graded relationship between different degrees of albuminuria
and CV events is unclear.
Our study examines the relationship between baseline albuminuria levels
and future CV events using data collected from individuals with or without
DM enrolled in the Heart Outcomes Prevention Evaluation (HOPE) Study. Participants
were followed-up for a median of 4.5 years
Participants and Overview of Study Design
Detailed descriptions of the HOPE study and MICRO (Microalbuminuria,
Cardiovascular and Renal Outcomes) HOPE substudy have been published previously.24-27 In
brief, individuals with or without DM aged 55 years or older with a history
of previous CV disease (either coronary artery disease, stroke, or peripheral
vascular disease) or with a history of DM plus at least 1 other CV risk factor
(total cholesterol >200 mg/dL [>5.2 mmol/L], high-density lipoprotein cholesterol ≤35
mg/dL [≤0.9 mmol/L], hypertension, known MA, or current smoker) were studied
between 1994 and 1999 in North and South America and Europe. Key exclusion
criteria included dipstick-positive proteinuria or established diabetic nephropathy,
other significant renal disease, hyperkalemia, CHF, low-ejection fraction,
or hypersensitivity to vitamin E or angiotensin-converting enzyme inhibitors.24 The aggregate primary end point of the study was
the development of either MI, stroke, or CV death. This analysis is restricted
to the 97% of all HOPE participants (3498 with DM and 5545 without DM) randomized
to receive either 10 mg of ramipril or placebo and in whom baseline urine
albumin measurements were available.
Diabetes status and other demographic and clinical variables were determined
by history and physical examination. Glycated hemoglobin was assayed for participants
with a history of DM in each study center's local laboratory. Results were
expressed as the percentage above the upper limit of normal for the assay
used. Serum creatinine was measured at each study site in all participants
at baseline and was only measured in the participants with DM at follow-up
visits. The results were expressed in International System of Units.
Urine Collection and Analysis
Urinary albumin was measured in 9043 (97%) of HOPE study participants
at baseline; the assays used have been described previously.24,25
A first morning urine was collected at baseline, 1 year, and study end. Urinary
albumin levels were measured by either radioassay (Europe and North America)
or immunoturbidimetry (South America), and urinary creatinine levels were
measured by the Jaffe method.25 The degree
of albuminuria, expressed as the albumin/creatinine ratio (ACR), was entered
into the database so that the relationship between baseline ACR and future
outcomes could be analyzed. Microalbuminuria was defined as an ACR of 2 mg/mmol
or more for both men and women; dipstick-positive (ie, ≥1 +) proteinuria
(ie, a level with >70% sensitivity and 90% specificity for detecting MA) was
an exclusion criteria.28
Participants were assessed every 6 months. Myocardial infarction, stroke,
CV death (the primary aggregate end point), and hospitalization for CHF (a
secondary end point), were documented and adjudicated centrally as described
previously. As reported, the study was approved by local ethics boards, and
all participants signed written informed consent.27
The univariate and multivariate relative risks (RRs) of the primary
study end point MI, stroke, or CV death; all-cause mortality; and hospitalization
for CHF in participants with and without MA were calculated using Cox regression
models. The proportionality assumption of the Cox model was assessed by inspection
of the Kaplan Meier curves for those with and without MA; these showed no
evidence of a time-dependent hazard. Variables entered into the multivariate
model for all participants included age, sex, smoking status, hypertension,
history of dyslipidemia (ie, a total cholesterol >200 mg/dL [>5.2 mmol/L]
or high-density lipoprotein cholesterol ≤35 mg/dL [≤0.9 mmol/L]), DM
status, abdominal obesity, and baseline serum creatinine level; for participants
with DM, duration of DM, use of oral glucose-lowering agents or insulin, and
glycated hemoglobin level were also included. Population attributable risk
for MA in all participants (ie, the proportion of events attributable to MA)
was estimated as the proportion of all people with MA × (the difference
in event rates between those with and without MA)/the overall event rate.
All participants were categorized by quartiles of albuminuria levels.
Tests for linear trend across quartiles were performed using Cox regression
after adjusting for (1) age and sex; (2) age, sex, systolic blood pressure,
diastolic blood pressure, waist-hip ratio, DM status (in all participants),
and glycated hemoglobin (in diabetic participants) in all the participants
and in those with no MA (ie, with an ACR <2 mg/mmol); and (3) randomization
to receive ramipril in the previous model. The unadjusted RR and 95% confidence
intervals (CIs) of outcomes in each quartile with reference to the first quartile
were also calculated. Model fit was assessed using the likelihood ratio test.
All statistical analyses were performed using SAS version 6.11.
Microalbuminuria was detected in 1140 (32.6%) of participants with DM
and 823 (14.8%) of participants without DM at baseline. A detailed description
of the baseline characteristics of the HOPE participants according to the
presence or absence of MA has been published previously.11
Both diabetic and nondiabetic individuals with MA were older, had higher systolic
and diastolic blood pressure, had a lower ankle-arm blood systolic pressure
ratio, and had a higher serum creatinine concentration than individuals without
MA; patients with DM and with MA also had a longer duration of DM and had
higher glycated hemoglobin level and waist-hip ratio than those without MA.
Table 1 and Table 2 list the incidence and risk of the primary aggregate end
point of the HOPE study MI, stroke, or CV death; all-cause mortality; and
hospitalization for CHF according to the presence of MA. After controlling
for randomization to receive ramipril, baseline MA increased the adjusted
RR for major CV events by 1.83-fold (95% CI, 1.64-2.05; P<.001); (2) all-cause mortality by 2.09-fold (95% CI, 1.84-2.38);
and (3) hospitalization for heart failure by 3.23-fold (95% CI, 2.54-4.10).
Similar estimates were noted in individuals with and without a history of
DM at the time of randomization (Table 1 and Table 2). The close
association between MA and these outcomes persisted even after controlling
for other CV risk factors in the placebo and ramipril groups (Table 2). The population attributable RRs were 12.7% (95% CI, 9.9%-15.5%)
for major CV events; 16.9% (95% CI, 13.4%-20.4%) for all-cause mortality;
and 31.1% (95% CI, 24.0%-38.3%) for hospitalization for heart failure.
Impact of ACRs Below the MA Threshold
These CV outcomes were also analyzed according to the level of albuminuria
(expressed in quartiles) to determine the CV importance of ACRs below the
MA threshold. The ACR cutpoints for each quartile of all HOPE participants
who had a baseline determination for albuminuria are shown in Table 3. There was a graded relationship between the baseline ACR
and the risk of both CV outcomes and mortality; this relationship extended
into the "submicroalbuminuric" range. For example, the RR of all-cause death
for each quartile compared with the first quartile (ACR <0.22 mg/mmol),
was 1.08 (95% CI, 0.89-1.42) for an ACR of 0.22 to 0.57 mg/mmol, 1.46 (95%
CI, 1.21-1.75) for an ACR of 0.58 to 1.62 mg/mmol, and 2.34 (95% CI, 1.99-2.77)
for an ACR >1.62 mg/mmol. For major CV events, all-cause mortality and hospitalization
for CHF in all participants, this linear trend was significant after (1) controlling
for age and sex (P<.001); (2) controlling for
age, sex, systolic blood pressure, diastolic blood pressure, waist-hip ratio,
and DM status (in all participants) or glycated hemoglobin in diabetic participants
(P<.001); and (3) after removing individuals with
MA and then controlling for age, sex, systolic blood pressure, diastolic blood
pressure, waist-hip ratio, and DM status in all participants or glycated hemoglobin
in participants with DM (P<.001 for major CV events
and all-cause mortality, and P = .05 for CHF hospitalization).
Similar findings were noted in the subgroups of participants with or without
DM (Table 3). Finally, the linear
trends remained significant when the 3 models were repeated for all participants
and for the subgroups of participants with or without DM after randomization
to receive ramipril was also included in the model (P
for trend <.001 except where indicated in Table 3).
The ACR as a Continuous Risk Factor
To further assess the ACR as a continuous CV risk factor, the incidence
of the primary outcome, all-cause death, and hospitalization for CHF was plotted
against the ACR (partitioned according to deciles in all participants with
a baseline measurement). Figure 1
illustrates the progressive nature of this relationship. In addition, the
hazard for these events for every increment in the ACR (by Cox regression)
was calculated after adjustment for age, sex, and randomization to receive
ramipril: for every 0.4-mg/mmol increase in ACR, the hazard of the primary
outcome increased by 5.9% (95% CI, 4.9-7.0); all-cause death increased by
6.8% (95% CI, 5.6-8.0%); and hospitalization for CHF increased by 10.6% (95%
CI, 8.4-13.0).
A growing number of prospective epidemiologic studies have reported
that MA is a strong independent risk factor for CV events.15-19
The data presented herein support this conclusion and also show that MA is
a strong independent risk factor for hospitalization for CHF and for all-cause
mortality in people with no prior history of CHF and show that the relationship
between albuminuria and experiencing a CV event is not restricted to the MA
range. Indeed, they indicate that the relationship between the ACR and CV
disease extends at least as low as 0.5 mg/mmol (Table 3), well below currently accepted screening thresholds for
a diagnosis of MA.29 This is consistent with
a recent prospective study in which individuals with an ACR of >0.65 mg/mmol
had an RR for ischemic heart disease of 2.3 (P =
.002) compared with people with a lower degree of albuminuria.30
Thus, an ACR of 2.0 mg/mmol—a threshold used to screen for MA and risk
for diabetic nephropathy—may not be relevant when considering the risk
for CV outcomes; lower degrees of albuminuria are also predictive.
Taken together these observations support the suggestion that albuminuria
reflects underlying vascular disease. These data also suggest that measurement
of urinary albumin may help estimate the absolute risk of experiencing a CV
event for individuals with or without DM. Patients with a high absolute risk
will experience a higher absolute risk reduction when given preventive interventions
than patients with a lower absolute risk. Therefore, a test that identifies
high-risk patients provides useful information that will help clinicians estimate
the benefits that may be expected from adding a proven preventive therapy.
Why is albuminuria a risk factor for CV disease? Clearly, a very small
concentration of urinary albumin is unlikely to be a direct cause. Albuminuria
is, however, associated with several other risk factors that may themselves
be causal or linked with causal processes. These include both diabetic and
nondiabetic degrees of hyperglycemia,31-33
hypertension,34,35 renal dysfunction,36 dyslipidemia,31 hyperhomocysteinemia,37 dietary protein,37
smoking,38 and markers of an acute phase response.39 Albuminuria also reveals increased renal endothelial
permeability and may be an easily measured marker of diffuse endothelial dysfunction.40 Thus albuminuria is an easily measured marker of
other CV factors, as well as existing endothelial dysfunction, that likely
reflects underlying macrovascular and microvascular disease.
The measurement of only 1 ACR at baseline and previous observations
that the degree of albuminuria varies from day-to-day are 2 limitations of
the data.41 Nevertheless, the large sample
size, central assay of the ACR, and the high diagnostic accuracy of a single
urine collection42-45
minimize the uncertainty associated with a single measurement. Moreover, the
regression dilution bias introduced by a single measurement of a risk factor
tends to underestimate the strength of the risk factor. This suggests that
the true association between ACR and CV events is likely to be even stronger
than observed in our study.46,47
Albuminuria is therefore a robust independent continuous risk factor
for future CV events, CHF, and all-cause mortality in middle-age dipstick-negative
individuals with or without DM at high risk for CV disease. It is also relatively
inexpensive and can be assayed for less than $10 in most laboratories. It
can therefore be used as a simple test to identify individuals at high risk
for future events who could be targeted for preventive strategies.
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