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MULTIPLE BIOMARKERS FOR THE
PREDICTION OF FIRST MAJOR

CARDIOVASCULAR EVENTS AND DEATH
Wang, Thomas J., et al., Massachusetts General
Hospital.,NEJM.
DR SHAHID HUSSAIN
OVERVIEW
To evaluate the incremental usefulness of

multiple biomarkers from various pathways.
Established risk factors, including smoking,

htn, DM, and dyslipidemia.
Significant interest in new biomarkers for risk

stratification of ambulatory persons.
NOVEL APPROACH
Many individual biomarkers have been

studied
Multimarker Approach
Simultaneous measurement may enhance

risk stratification?
OUTCOMES ANALYSIS
Death from any cause
1st Major cardiovascular event (MI, coronary

insufficiency, heart failure, and stroke.
Reviewed by a committee of three

investigators
STUDY SAMPLE
Large, community based cohort study
Participants from the sixth examination cycle

(1995-1998) of the Framingham Offspring Study
IRB of Boston University Medical Center approval
Written informed consent was obtained
EXCLUSION CRITERIA
Serum creatinine levels greater than 2.0 mg/dL
Missing covariates
Prior event when determining outcome of major

cardiovascular event
Triglycerides > 400
BIOMARKER SELECTION
1. Marker of inflammation- hsCRP
2. Markers of neurohormonal activity- BNP,

aldosterone, renin, N-terminal pro-atrial
natriuretic peptide
3. Marker of thrombosis and inflammation- fibrinogen
4. Marker of fibrinolytic potential and endothelial

function- plasminogen-activator (Inhibitor type 1)
BIOMARKER CONTD
5. Marker of thrombosis- D-dimer
6. Marker of endotheial function and oxidant

stress- homocysteine
7. Marker of glomerular endothelial functionurinary albumin-to-creatinine ratio
LAB PROTOCOL
Fasting blood and urine samples collected in

morning after patient supine for ~10
minutes. Immediately centrifuged and
stored at -70 C
Standardized Assay Methods
STATISTICAL ANALYSIS
Multivariable proportional-hazards model (2

sets of analyses for each outcome due to
urine subgroups)
Logarithmic transformation used to normalize

the distribution of biomarkers
To reduce the number of false positives from

multiple testing:
STATISTICS CONTD
1) Multivariable Cox regression model
2) Backward elimination
3) Construction of multimarker score
4) Quintiles categorized
5) Cumulative probability curves constructed by the KaplanMeier method for low, intermediate and high mulitmarker
scores
RESULTS
Total of 3532 persons- 21 excluded for serum creatinine

and 302 for missing covariates.
10 year follow-up (median 7.4 years) 3209 available for

study.
207 (6%) died, of whom 72 were women
169 (6%, excluding prevalent CV disease at baseline) had

a major cardiovascular event, of whom 68 were women
RESULTS CONTD
Biomarker panel for nine: P<0.001 for death

and P=0.005 for cardiovascular events
Biomarker panel for ten (2750 persons):

P<0.001 for death and P=0.04 for
cardiovascular events
RESULTS CONTD
Backward elimination models: final statistical

model included only the following biomarkers:
BNP, homocysteine, urinary albumin-tocreatinine ratio and renin for death.

BNP and urinary albumin-to-creatinine ratio for
major cardiovascular events.
UTILITY OF MULTIMARKER SCORES
Backward elimination biomarkers selected as

statistically significant were incorporated into
mulitmarker scores.
Restricted to urine sample patients:
1) death from any cause, the number of events and

number at risk were 172 and 2750, respectively;
2) major cardiovascular events, 133 and 2598,
respectively.
UTILITY?
Persons with high multimarker scores had a

risk of death four times as great and a risk of
major cariovascular events almost two times
as great as persons with low mulitmarker
scores.
(P<0.001 and P=0.02, respectively)
DISCUSSION
~10 year study of biomarkers indicating BNP,

hsCRP, homocysteine, renin, and alb/Cr ratio as
most informative for predicting death,
BNP and alb/Cr ration as significant for predicting

cardiovascular outcome.
Although high multimarker scores conferred

greater risk for death and major cardiovascular
events
CONCLUSION
Mulitmarker scores (combination of biomarkers)

add only moderately to conventional risk factors
as evidenced by small changes in C statistic.
Single biomarkers may have correlation with

predicting outcomes
Panel likely will not be useful or cost-effective in

ambulatory setting for further risk stratification
LIMITATIONS
Biomarker selection: omission of lipoproteinassociated phospholipase A2
Each individual marker not independently tested
Not a true cohort study to asses for primary

prevention as nonmajor cardiovascular events
adjusted
Adiposity or insulin resistance not taken into account
SUMMARY
Biomarkers from multiple, biologically distinct

pathways are associated with the risks of
death and major cardiovascular events.
However, only moderately adds to

conventional risk factors currently.

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MULTIPLE BIOMARKERS FOR THE

PREDICTION OF FIRST MAJOR

To evaluate the incremental usefulness of

Established risk factors, including smoking,

Significant interest in new biomarkers for risk

Many individual biomarkers have been

Simultaneous measurement may enhance

Death from any cause

1st Major cardiovascular event (MI, coronary

Reviewed by a committee of three

Large, community based cohort study

Participants from the sixth examination cycle

IRB of Boston University Medical Center approval

Written informed consent was obtained

Serum creatinine levels greater than 2.0 mg/dL

Prior event when determining outcome of major

Triglycerides > 400

1. Marker of inflammation- hsCRP

2. Markers of neurohormonal activity- BNP,

3. Marker of thrombosis and inflammation- fibrinogen

4. Marker of fibrinolytic potential and endothelial

5. Marker of thrombosis- D-dimer

6. Marker of endotheial function and oxidant

7. Marker of glomerular endothelial functionurinary albumin-to-creatinine ratio

Fasting blood and urine samples collected in

Standardized Assay Methods

Multivariable proportional-hazards model (2

Logarithmic transformation used to normalize

To reduce the number of false positives from

1) Multivariable Cox regression model

3) Construction of multimarker score

Total of 3532 persons- 21 excluded for serum creatinine

10 year follow-up (median 7.4 years) 3209 available for

207 (6%) died, of whom 72 were women

169 (6%, excluding prevalent CV disease at baseline) had

Biomarker panel for nine: P<0.001 for death

Biomarker panel for ten (2750 persons):

Backward elimination models: final statistical

BNP, homocysteine, urinary albumin-tocreatinine ratio and renin for death.

UTILITY OF MULTIMARKER SCORES

Backward elimination biomarkers selected as

Restricted to urine sample patients:

1) death from any cause, the number of events and

Persons with high multimarker scores had a

(P<0.001 and P=0.02, respectively)

~10 year study of biomarkers indicating BNP,

BNP and alb/Cr ration as significant for predicting

Although high multimarker scores conferred

Mulitmarker scores (combination of biomarkers)

Single biomarkers may have correlation with

Panel likely will not be useful or cost-effective in

Biomarker selection: omission of lipoproteinassociated phospholipase A2

Each individual marker not independently tested

Not a true cohort study to asses for primary

Adiposity or insulin resistance not taken into account

Biomarkers from multiple, biologically distinct

However, only moderately adds to

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