The grey zone: What to do for the
“intermediate risk” patient?
Lifestyle-Heart Hypothesis
Mozaffarian et al. Circulation 2008;117;3031-3038
Atherosclerosis:
Traditional and novel risk factors
• Interheart: Developed and developing countries (N = approx 30,000)
• IHD Risk Factor
Odds Ratio
Population
attributable risk
• ApoB/ApoAI
3.25
49%
• Smoking
2.87
36%
• Hypertension
1.91
18%
• Diabetes
2.37
10%
• Abdominal obesity
1.12 – 1.62
20%
• Psychosocial
2.67
33%
• Diet (fruit & veg)
0.70
14%
• Activity
0.86
12%
• Alcohol (not binge)
0.91
7%
Atheroma: Stages and timeframe
Atheroma is proportional to the number
and severity of classic risk factors
Where is my
patient?
Novel risk factors and atheroma
Lumen
Development of an atheroma
LDL-C, β-VLDL, Lp(a)
Monocyte
Adhesion
VCAM-1
ICAM-1
P-selectin
E-selectin
Migration
MCP-1
CCR-2
oxLDL
Cytokines
MMPs
Endothelin-1
Induction of adhesion
molecules and chemotaxis
oxidation
Differentiation
(GM-CSF)
CD36
SR-A
Intima
Endothelial
cells
T lymphocyte
CD40
IFN-gamma
Foam cell
Macrophage
ß-VLDL = beta-very low-density lipoprotein; Lp(a) = lipoprotein (a); VCAM-1 = vascular cell adhesion molecule-1; ICAM-1 = intercellular adhesion molecule1; MCP-1 = monocyte chemoattractant protein-1; CCR-2 = specific receptor present on the surface of monocytes; oxLDL = oxidized low-density lipoprotein;
MMP = matrix metalloproteinases; GM-CSF = granulocyte macrophage-colony stimulating factor; SR-A = macrophage scavenger receptor class A
Adapted with permission from Fan et al, J Atheroscler Thromb 2003; 10: 63
Integration of risk factors: Risk calculators
Limitations of CVD Risk Assessment
• Underlying data (eg FRS) is historical, geographical
• Suitable for non-western populations in 21st century?
• Some data components are infrequently available
• Left ventricular hypertrophy
• No mechanism to take advantage of risk predictors
• High sensitivity C-reactive protein etc
• Predominant effect of age
• Assigns low 10-year risk to some patients with moderate to
high lifetime risk who might benefit from more aggressive
management, particularly in women & younger men
• Omits or fails to quantify several major risk factors
• Family history, smoking, diabetes.
High sensitivity C-reactive protein as a
discriminator in intermediate risk?
US Preventive Services Task Force (2009)

“CRP is associated with CHD events....Adding CRP to risk
prediction models among initially intermediate risk persons
improved risk stratification. However.. evidence that reducing
CRP levels prevents CHD is lacking” “ the current evidence
is insufficient to assess the balance of benefits and harms of
using the non-traditional risk factors studied to screen
asymptomatic men and women with no history of CHD to
prevent CHD events.”
American Heart Assoc and CDC (2008)
“the entire adult population should not be screened for hsCRP for the purposes of CVD risk assessment.”
Additional analytes, improved assays or evidence of benefits
of combinations of assays may in future be found to have
advantages, but further research is needed”
Canadian Cardiovascular Society (2009)
“men older than 50 years and women older than 60 years of
age, of intermediate risk whose LDL-C does not already
suggest treatment, hs-CRP can be used for risk stratification”
Clinical risks: Microalbuminuria, renal
impairment and inflammatory disorders
Markers of end-organ damage
BNP
Hs-TnT
Genetic evidence for additional risks factors
Non-invasive imaging detects sub-clinical
atheroma
Shaw et al. Radiology 2003; 228:826-833
Raggi P et al. Arterioscler Thromb Vasc Biol. 2004;24:1272-77
Primary
Author
Study Type
Shaw L 2
Observational
1
Kondos G
Greenland P
Observational
Prospective
5
LaMonte M 6
Arad Y 4
Taylor A
Becker A
Prospective
7
Detrano R
Prospective
Prospective
8
9
Prospective
Prospective
No of
Patients
10,377
Mean
Follow-up
(years)
Type of Events
No
of
events
Incremental
Prognostic
Value of
Coronary
Calcium
5
All-cause death
249
Yes
5,635
3
Myocardial Infarction,
Death and
Revascularizations
224
Not Assessed
1,029
7.0 (median)
Myocardial Infarction
and Death
84
Yes
81
Yes
Myocardial Infarction
and Cardiovascular
Death
10,746
3.5
4,613
4.3
Atherosclerotic
Cardiovascular Events
119
Yes
3
Acute Coronary
Syndrome and Sudden
Cardiac Death
9
Yes
3.8
Myocardial Infarction
and Cardiovascular
Death
89
Yes
3.4
Myocardial Infarction
and Cardiovascular
Death
179
Yes
1,983
6,722
1,726
Reclassification of intermediate risk patients
Where to set the risk threshold?
Benefit versus risk or benefit versus cost?
“If statins cost $4/month, treatment thresholds of low-density lipoprotein cholesterol > 4 mmol/l
for low-risk persons (0 to 1 risk factor), >3.3 mmol/l for moderate-risk persons (≥2 risk factors
and 10-year risk <10%), and >2.6 mg/dL for moderately high-risk persons (≥2 risk factors and
10-year risk >10%) would reduce annual healthcare costs by $430 million compared with
Adult Treatment Panel III guidelines”. Lazar LD. Circ 124:146-53
Strategies that compete with the
absolute risk approach.
Establishing a risk factor
• Epidemiological methods identify risk factors
• The more independent risk factors for a
outcome / disease, the worse each is
likely to perform on its own as a predictor
• What matters is the amount of the total risk
attributable to the risk factor
Establishing a risk factor
Lowest fifth
Highest fifth
Establishing a risk factor
Incidence ratio = (50/1000) / (5/1000) = 10
Odds ratio = (50/950) / (5/995)  10
Rate of disease = 50 / 1000
Rate of disease = 5 / 1000
Establishing a risk factor
60% of the
population!
1. Law MR, Watt HC, Wald NJ,.
1. Law MR, Watt HC, Wald NJ,.
Threshold risk factor
Threshold
Continuous risk factor
No threshold
What happens when you treat?
O.R.
x?
x
Cholesterol
Summary and transition to cases
• deCODE MI re class, 2 cases
• Complex cases 1
O.R.
Cholesterol reduction
Reduction in risk in treatment
group
Incidence of
major coronary
events in
placebo group
(%/yr)
Relative (%)
Absolute
(%/yr)
Trial
Net
change
in TC
WOSCOPS
1.7
mmol/L
1.4
39 (20 – 52)
0.5 (0.3 –
0.7)*
4S
1.4
mmol/L
5.2
35 (27 – 42)
1.8 (1.4 –
2.2)*
1. Shepherd J, Cobbe S, et al., Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.
West of Scotland Coronary Prevention Study Group. New England Journal of Medicine, 1995. 333(20):1301.
Cholesterol reduction
Reduction in risk in treatment
group
Incidence of
major coronary
events in
placebo group
(%/yr)
Relative (%)
Absolute
(%/yr)
Trial
Net
change
in TC
WOSCOPS
1.7
mmol/L
1.4
39 (20 – 52)
0.5 (0.3 –
0.7)*
4S
1.4
mmol/L
5.2
35 (27 – 42)
1.8 (1.4 –
2.2)*
1. Scandinavian Simvastatin Survival Study Group, Randomised trial of cholesterol lowering in 4444 patients with
coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet, 1994. 344(8934):1383.
Cholesterol reduction
Reduction in risk in treatment
group
Incidence of
major coronary
events in
placebo group
(%/yr)
Relative (%)
Absolute
(%/yr)
Trial
Net
change
in TC
WOSCOPS
1.7
mmol/L
1.4
39 (20 – 52)
0.5 (0.3 –
0.7)*
4S
1.4
mmol/L
5.2
35 (27 – 42)
1.8 (1.4 –
2.2)*
Systolic blood pressure
Floating Absolute Risk & 95% CI
8.00
4.00
2.00
1.00
0.50
0.25
110
120
130
140
150
160
170
Usual SBP (mmHg)
1. Asia-Pacific Cohort Studies Collaboration, Randomised trial of cholesterol lowering in 4444 patients with coronary heart
disease: the Scandinavian Simvastatin Survival Study (4S). Lancet, 1994. 344(8934):1383.
Diastolic blood pressure
Odds ratio for CHD
Coronary disease
O.R.
Stroke
Usual diastolic blood pressure (mmHg)
MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, et al. Blood pressure, stroke and coronary heart disease.
1. Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias.
Lancet 1990;335:76574.
Diastolic blood pressure
Odds ratio for CHD
Coronary disease
O.R.
Stroke
Usual diastolic blood pressure (mmHg)
MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, et al. Blood pressure, stroke and coronary heart disease.
1. Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias.
Lancet 1990;335:76574.
Smoking
Yusuf S, Hawken S, et al. 2004: Effect of potentially modifiable risk factors associated with myocardial infarction
in 52 countries (the INTERHEART study): case-control study. Lancet, 364(9438): p. 937.
Yusuf S, Hawken S, et al. 2004: Effect of potentially modifiable risk factors
associated with myocardial infarction in 52 countries (the INTERHEART study):
case-control study. Lancet, 364(9438): p. 937.
Attributable risk
7,000
4000
3000
6,000
5,000
3000
2000
4,000
2000
3,000
1000
2,000
1000
1,000
-
0
0
100 120 140 160 180 200
Systolic blood pressure (mmHg)
1. Law MR, Watt HC, Wald NJ,.
3.8 4.4 5.1 5.7 6.3 7.0 7.6
Cholesterol (mmol/l)
20 23 26 29 32 35 38 41 44
Body mass index (kg/m2)
Framingham equation
• = 0 + 1 x female + 2 x log(age) + 3 x log(age)
x female + 4 x [log(age)]2 x female + 5 x
log(SBP) + 6 x cigarettes + 7 x log(TC/HDL) +
8 x diabetes + 9 x diabetes x female + 10 LVH
•  = exp(0 + 1 )
• u = [log(10)] - ] / 
• 10 y predicted P for CHD = 1 – exp(-exp(u))
Framingham equation
• = 0 + 1 x female + 2 x log(age) + 3 x log(age)
x female + 4 x [log(age)]2 x female + 5 x
log(SBP) + 6 x cigarettes + 7 x log(TC/HDL) +
8 x diabetes + 9 x diabetes x female + 10 LVH
•  = exp(0 + 1 )
• u = [log(10)] - ] / 
• 10 y predicted P for CHD = 1 – exp(-exp(u))
Framingham equation mismatches
0.10
CHD death rate
0.08
Observed
0.06
Framingham
0.04
0.02
0
1
2
3
4
5
6
7
8
9
10
0.010
Framingham
equation recalibration
0.000
1
2
3
4
5
6
7
8
9
10
7
8
9
10
0.10
CHD death rate
0.08
Observed
0.06
Framingham
0.04
Framingham calibrated
0.02
0
1
2
3
4
5
6
Limitations
• Underestimates for extremes of risk factors
• Younger people have lower risk
• But more life years lost
• Consider projecting risk forward in time
• Normalising for age
• New/novel risk factors
•
•
•
•
•
•
Continuous HbA1c
hsCRP
Lp(a)
Apo E4/E4
Obesity
CKD
Implications of global risk approach
Treat anyone at high risk
1. Law MR, Watt HC, Wald NJ, The Underlying Risk of Death After Myocardial Infarction in the Absence of Treatment.
Archives of Internal Medicine, 2002;162(21):2405.
The major determinant of risk is
existing disease
Treat anyone at high risk
• Untreated MI:
• Death rates for first event: 36%
• Before hospital 23%
• During admission 16% (of those admitted)
• Subsequent events: 53%
• Before hospital 33%
• During admission 30%
1. Law MR, Watt HC, Wald NJ, The Underlying Risk of Death After Myocardial Infarction in the Absence of Treatment.
Archives of Internal Medicine, 2002;162(21):2405.
The major determinant of risk is
existing disease
Treat anyone at high risk
• Untreated MI: First event
• Death rates for first year: 10.3%
• Stroke & heart disease 9.6%
• Annual death rate 5.3% (for life)
• Stroke & heart disease 4.6%
• Subsequent events:
• First year 21% (19% CVD)
• Annual death rate 12% (10% CVD)
1. Law MR, Watt HC, Wald NJ, The Underlying Risk of Death After Myocardial Infarction in the Absence of Treatment.
Archives of Internal Medicine, 2002;162(21):2405.
Implications of global risk approach
Change all the risk factors together
 Not just the “abnormal” ones
10.0%
10.0%
25%
9.0%
7.5%
8.0%
>50%
25%
7.0%
5.6%
6.0%
5.0%
4.2%
4.0%
3.0%
2.0%
1.0%
0.0%
0
1
2
3
The major determinant of risk is
existing disease
Treat anyone at high risk
1. Australian Institute of Health and Welfare. Heart, stroke and vascular diseases: Australian Facts 2004. AIHW.
fixrhubarbzumab
Don’t do unnecessary trials
?
Don’t do unnecessary trials
Don’t do unnecessary trials
Adapted from:
Law MR, Wald NJ, Risk factor thresholds: their existence under scrutiny. BMJ, 2002;324:1570.
Cost efficacy
80%
80%
70%
70%
60%
60%
50%
50%
40%
40%
30%
30%
20%
20%
10%
10%
0%
0%
-10%
-20%
10% risk
15% risk
20% risk
-10%
-20%
Mr J.S.
• Mr J.S. has a history consistent with Familial Combined Hyperlipidaemia. He
is 49 years old, BP 150/90 and his lipids include: TC = 7.8 mmol/l, TG = 2.7
mmol/l, HDL = 1.1 mmol/l, LDL = 5.6 mmol/l. His older brother, who, like J.S,
was a non smoker, suffered onset of CVD at this age. J.S.’s total CVD risk is
14%
Questions concerning Mr J.S.
• Does he warrant lipid-lowering treatment according to NHF guidelines?
Yes / No
• A colleague suggests that his ankle:brachial index should be measured. Is
this non invasive test for CVD risk A) Specific B) Sensitive
C) Both
• Could his risk assessment be improved by Genome Wide Association
Studies?
Yes / No
• Mr J.S. has a history consistent with Familial Combined Hyperlipidaemia. He
is 49 years old, BP 150/90 and his lipids include: TC = 7.8 mmol/l, TG = 2.7
mmol/l, HDL = 1.1 mmol/l, LDL = 5.6 mmol/l. His older brother, who, like J.S,
was a non smoker, suffered onset of CVD at this age. J.S.’s total CVD risk is
14%
• Does he warrant lipid-lowering treatment according to NHF guidelines?
Yes / No
• A colleague suggests that his ankle:brachial index should be measured. Is
this non invasive test for CVD risk A) Specific B) Sensitive
C) Both
• Could his risk assessment be improved by Genome Wide Association
Studies?
Yes / No
Does he warrant lipid-lowering treatment
according to NHF guidelines?
• Yes
• No
Does he warrant lipid-lowering treatment
according to NHF guidelines?
The case for “Yes”
Others with elevated absolute risk of CVD
Lipid-modifying therapy is indicated for those with: C
◦ absolute risk ≥15% of a CVD event in the next 5 years or
◦ absolute risk 10–15% of a CVD event in the next 5 years when either
of the following is present:
- family history of premature CHD (first degree relative who developed
CHD before age 60)
-the metabolic syndrome
2005 Update of NHF Lipid Management Guidelines
A colleague suggests that his ankle:brachial
index should be measured. Is this noninvasive test for CVD risk...
• : A) Specific
• B) Sensitive
• C) Both
A colleague suggests that his ankle:brachial
index should be measured. Is this noninvasive test for CVD risk...
The case for “A”
Arteriosclerosis, Thrombosis, and Vascular Biology.2005; 25: 1463-146
Sensitivity and Specificity of the Ankle–Brachial Index to Predict
Future Cardiovascular Outcomes A Systematic Review
Anand V. Doobay, Sonia S. Anand
The sensitivity and specificity of a low ankle–brachial index to predict
incident coronary heart diseases were 16.5% and 92.7%, for incident
stroke were 16.0% and 92.2%, and for cardiovascular mortality were
41.0% and 87.9%, respectively. The corresponding positive likelihood
ratios were 2.53 (95% CI, 1.45 to 4.40) for coronary heart disease, 2.45
(95% CI, 1.76 to 3.41) for stroke, and 5.61 (95% CI, 3.45 to 9.13) for
cardiovascular death.
Could his risk assessment be improved by
Genome Wide Association Studies?
• Yes
• No
The deCODEme Complete Scan identifies validated MI risk variants and uses them to provide a personalized interpretation of the associated genetic risk for having a heart attack. T
Could his risk assessment be improved by
Genome Wide Association Studies?
The case for “No”?
Number of Variants
Measured
European ancestry
16
East Asian ancestry
3
Samani N et al, N Engl J Med 2007; 357:443-453.
C
N (%)
G
N (%)
Cases
2,132 (55.4)
1,716 (44.6)
Controls
2,783 (47.4)
3,089 (52.6)
2
(1df)
P-value
55.1
1.2 x 10-13
2
(2df)
P-value
59.7
1.1 x 10-14
Allelic Odds Ratio = 1.38
CC
N (%)
CG
N (%)
GG
N (%)
Cases
586 (30.5)
960 (49.9)
378 (19.6)
Controls
676 (23.0)
1,431 (48.7)
829 (28.2)
Heterozygote Odds Ratio = 1.47
Homozygote Odds Ratio = 1.90
Mr J.S (continued).
• Mr J.S does not have chest pain or any exertional symptoms, but he had an
anaphylactic reaction, which may have been related to the introduction of
statins.
• He remained off statin, but then developed atypical chest pain.
More questions regarding Mr J.S.
• Which non-invasive test would you favour to weigh up risks versus benefits
of re-attempting statin therapy?
A) CT
coronary angiogram B) Sestamibi perfusion scan
C) Stress Echo D)
Coronary Calcium Score
E) Exercise ECG
• Which of the previous tests would you be prepared to repeat on a 2 to 3
yearly basis? (more than 1 possible)
A) CT coronary angiogram B) Sestamibi perfusion scan
C) Stress
Echo
D) Coronary Calcium Score
E) Exercise ECG
He underwent CT coronary angiogram which suggested 70% stenosis in 2
vessels. Does CT coronary angiography tend to underestimate or
overestimate disease severity?
Underestimate / Overestimate / Neither
• Mr J.S does not have chest pain or any exertional symptoms, but he had an
anaphylactic reaction, which may have been related to the introduction of
statins. Which non-invasive test would you favour to weigh up risks versus
benefits of re-attempting statin therapy?
A) CT coronary angiogram
B) Sestamibi perfusion scan
C)
Stress Echo D) Coronary Calcium Score
E) Exercise ECG
• If he remained off statin, which of the previous tests would you be prepared
to repeat on a 2 to 3 yearly basis? (more than 1 possible)
A) CT coronary angiogram B) Sestamibi perfusion scan
C) Stress
Echo
D) Coronary Calcium Score
E) Exercise ECG
Mr J.S. Developed atypical chest pain and underwent CT coronary
angiogram which suggested 70% stenosis in 2 vessels. Does CT coronary
angiography tend to underestimate or overestimate disease severity?
Underestimate / Overestimate / Neither
Mr J.S does not have chest pain or any
exertional symptoms, but he had an
anaphylactic reaction, which may have been
related to the introduction of statins. Which
non-invasive test would you favour to weigh
up risks versus benefits of re-attempting
statin therapy?
• A) CT coronary angiogram
•
• B) Sestamibi perfusion scan
•
• C) Stress Echo
• D) Coronary Calcium Score
•
• E) Exercise ECG
Mr J.S does not have chest pain or any
exertional symptoms, but he had an
anaphyllactic reaction, which may have been
related to the introduction of statins. Which
non-invasive test would you favour to weigh
up risks versus benefits of re-attempting
statin therapy?
The case for “D”, but “C” and “E” reasonable
If he remained off statin, which of the
previous tests would you be prepared to
repeat on a 2 to 3 yearly basis? (more than 1
possible)
A) CT coronary angiogram
B) Sestamibi perfusion scan
C) Stress Echo
D) Coronary Calcium Score
E) Exercise ECG
If he remained off statin, which of the
previous tests would you be prepared to
repeat on a 2 to 3 yearly basis?
The case for “D” (“C” and “E” reasonable)
Mr J.S. developed atypical chest pain and
underwent CT coronary angiogram which
suggested 70% stenosis in 2 vessels. Does
CT coronary angiography tend to
underestimate or overestimate disease
severity?
Underestimate
Overestimate.
Neither
Mr J.S. developed atypical chest pain and
underwent CT coronary angiogram which
suggested 70% stenosis in 2 vessels. Does
CT coronary angiography tend to
underestimate or overestimate disease
severity?
The case for “B”
Heart 2011;97:1363-1364 CT coronary angiography: a new unique prognosticator?
Lisan A Neefjes, Pim J de Feyter.
CTCA tends to overestimate the severity of the coronary stenosis, resulting in a number
of patients with false-positive outcomes that is too high. This is mainly caused by the
blooming effect of calcified lesions in combination with the still too limited spatial
resolution of CTCA as compared with invasive coronary angiography. CTCA provides,
additional to luminography, comprehensive assessment of the anatomical manifestations
of coronary atherosclerosis, including the distribution (proximal, mid and distal) and
extent (one-, two-, three-vessel disease, left main disease) of CAD, the presence of
‘positive remodelling’ of the vessel and a, rather crude, assessment of the coronary
plaque components (calcified, non-calcified and mixed)
Ms A.Y.
• Ms A.Y is a 53 year-old woman with a 20 year history of severe rheumatoid
arthritis. She is suffering a flare-up despite systemic steroid therapy and
steroid sparing agents. Central chest pain is consistent with pericarditis, but
cardiovascular risk assessment is thought to be justified. BP (115/75) is
normal but creatinine is mildly elevated (112 umol/l). TC = 5.7, TG = 2.6,
HDL = 0.9 mmol/l, LDL = 3.6 mmol/l. Family history is unremarkable but
uncertainty concerning her risk prompts measurement of hs-CRP (5 mg/l),
lipoprotein (a), (678 mg/l) and total homocysteine, (23 umol/l) all of which are
elevated.
Questions concerning Ms A.Y.
• Calculated 5 year risk is 2%. Do you agree with this estimation? Yes / No
• Which of the following is unlikely to be affected by the inflammatory state?
A) Lipid profile B) hs-CRP C) Lipoprotein (a) D) homocysteine
• Which of the following is less likely to be affected by the renal impairment?
A) Lipid profile B) hs-CRP C) Lipoprotein (a) D) homocysteine
• How much is Ms A.Y’s RELATIVE risk of CVD increased? A) 20%
50%
C) 100%
D) 200%
E) More than 200%
B)
• Ms A.Y is a 53 year-old woman with a 20 year history of severe rheumatoid
arthritis. She is suffering a flare-up despite systemic steroid therapy and
steroid sparing agents. Central chest pain is consistent with pericarditis, but
cardiovascular risk assessment is thought to be justified. BP (115/75) is
normal but creatinine is mildly elevated (112 umol/l). TC = 5.7, TG = 2.6,
HDL = 0.9 mmol/l, LDL = 3.6 mmol/l. Family history is unremarkable but
uncertainty concerning her risk prompts measurement of hs-CRP (5 mg/l),
lipoprotein (a), (678 mg/l) and total homocysteine, (23 umol/l) all of which are
elevated.
• Calculated 5 year risk is 2%. Do you agree with this estimation? Yes / No
• Which of the following is less likely to be affected by the inflammatory state?
A) Lipid profile B) hs-CRP C) Lipoprotein (a) D) homocysteine
• Which of the following is unlikely to be affected by the renal impairment? A)
Lipid profile B) hs-CRP C) Lipoprotein (a) D) homocysteine
• How much is Ms A.Y’s RELATIVE risk of CVD increased? A) 20%
50%
C) 100%
D) 200%
E) More than 200%
B)
Calculated 5 year risk is 2%. Do you
agree with this estimation?
• Yes
• No
Calculated 5 year risk is 2%. Do you
agree with this estimation?
The case for “No”
Study
n
OR (SMR)
ORALE1
236
3.17 (adj)
Rochester Cohort2
603
2.12 (MI)
Nurses Health Study3
527
2.0
Stockport Inception cohort4
1010
1.93
-
1.70 overall
mortality
Van Doornum et al.5
Maradit-Kremers H, et al. Arthritis Rheum 2005; 52:722–732; 3. Solomon DH, et al. Circulation 2003; 107:1303–
1307; 4. Goodson N, et al. Ann Rheum Dis 2005; 64:1595–601; 5. Van Doornum S, et al. Arthritis Rheum 2002;
46: 862–73
Which of the following is less likely to
be affected by the inflammatory state?
• A) Lipid profile
• B) hs-CRP
• C) Lipoprotein (a)
• D) homocysteine
• E) None of the above
Which of the following is less likely to be
affected by the inflammatory state?
The case for “E”
Circulating Homocysteine Is An Inflammation Marker
And A Risk Factor of Life-Threatening Inflammatory Diseases
J Biomed Lab Sci 2007 James T. Wu
Deficiency in vitamin B6, B12 or folate is the major cause of
hyperhomocysteinemia. Since inflammation promotes cell proliferation
at the expense of excess amount of vitamins, therefore,
hyperhomocysteinemia may indicate the presence of inflammation.
Moreover, inflammation enhances the synthesis of nitric oxide, which
again produces hyperhomocysteinemia through binding with
vitamin B12. Consequently, varying degrees of hyperhomocysteinemia
are detectable in all inflammatory diseases
Which of the following is unlikely to be
affected by the renal impairment?
• A) Lipid profile
• B) hs-CRP
• C) Lipoprotein (a)
• D) homocysteine
• E) None of the above
Which of the following is unlikely to be
affected by the renal impairment?
The case for “E”
C-reactive protein, cardiovascular risk, and renal disease in a remote Australian
Aboriginal community. Clinical Science 106, 121–128
Stephen McDONALD, Graeme MAGUIRE, Natalia DUARTE, Xing Li WANG and
Wendy HOY
Higher CRP concentrations were associated with the following:
45–54-year age group, female subjects, the presence of skin sores, higher body mass
index, waist circumference, BP, glycated haemoglobin and greater albuminuria. CRP
concentrations increased with the number of cardiovascular risk factors, carotid IMT
and albuminuria independently of other risk factors. These CRP concentrations were
markedly higher than described in other community settings and are probably related, in
a large part, to chronic and repeated infections.
Their association with markers of cardiovascular risk and renal disease are compatible
with the high rates of cardiovascular and renal disease in this community, and provide
more evidence of strong links between these conditions, through a shared background
of infection/inflammation
How much is Ms A.Y’s RELATIVE risk
of CVD increased?
A) 20%
• B) 50%
• C) 100%
• D) 200%
• E) More than 200%
How much is Ms A.Y’s RELATIVE risk
of CVD increased?
The case for “D-E”
Del Rincon (n=236)
CV events (95% CI)
Age- and sex-adjusted
3.96 (1.86–8.43)
After adjusting for CV risk factors
using Poisson regression
3.17 (1.33–6.36)
Del Rincón I, et al. Arthritis Rheum 2001; 44:2737–2745; 2.
Ms A.Y.
• Ms A.Y is commenced on anti-TNF alpha therapy for her rheumatological
condition.
More questions concerning Ms A.Y.
• Ms A.Y is commenced on anti-TNF alpha therapy for her rheumatological
condition.
• Which of the following lipids or lipoproteins is NOT likely to increase in
response to anti-TNF therapy (Adalimumab (Humira))?
A) LDL particle number B) HDL-C C) TG D) LDL-C E) Lp (a)
• Evidence suggests this treatment improves A) Vascular reactivity B) CVD
morbidity
C) Both A and B
D) All aspects of the lipid profile
• Is folic acid therapy warranted in order to reduce homocysteine? Yes / No
• Do statins and Humira have identical effects on lipids and CVD risk? Yes /
No
Which of the following lipids or lipoproteins is
NOT likely to increase in response to anti-TNF
therapy (Adalimumab (Humira))?
(2 correct answers)
• A) LDL particle size
• B) HDL-C
• C) TG
• D) LDL-C
• E) Lp (a)
Which of the following lipids or lipoproteins is
NOT likely to increase in response to anti-TNF
therapy (Adalimumab (Humira))?
The case for “E”
Lipids and Cardiovascular Risk in Rheumatoid Arthritis
Increases from baseline in mean total cholesterol, low-density lipoprotein
(LDL), high-density lipoprotein (HDL), triglycerides, and apolipoprotein
A1 and B levels -- unlike typical dyslipidemia (increased LDL and
decreased HDL) -- were observed within 6 weeks of treatment initiation.
These levels persisted to week 24 in patients treated with TCZ.
Concurrent substantial reductions from baseline in mean levels of several
inflammatory biomarkers, including C-reactive protein (CRP), serum
amyloid A (SAA), haptoglobin, and lipoprotein(a), were also observed in
patients treated with TCZ.
Evidence suggests this treatment improves
• A) Vascular reactivity
• B) CVD morbidity
• C) Both A and B
• D) All aspects of the lipid profile
Evidence suggests this treatment improves
The case for “B”. No data on “A”
Anti-TNF Use Linked to Cardiovascular-Disease Drop in RA
MITCHEL L. ZOLER
In both studies, treatment with an anti-TNF agent was linked to a
statistically significant cut in cardiovascular (CV) events of about 50%.
These results support another recent, similar finding reported in June at
the Annual European Congress of Rheumatology in London. In that
study, analysis of medical records from more than 109,000 U.S. patients
with RA showed that every 6 months of treatment with an anti-TNF
drug reduced the rate of CV events by 13%, compared with RA patients
who did not receive a TNF blocker.
Is folic acid therapy warranted in order
to reduce homocysteine?
• Yes
• No
Is folic acid therapy warranted in order to
reduce homocysteine?
The “State of Play” favours “No”
Do statins and Humira have identical effects
on lipids and CVD risk?
• Yes
• No
Do statins and Humira have identical effects
on lipids and CVD risk?
The case for “No”
Ann Rheum Dis 2007;66:1503-1507 Modulation of lipoprotein plasma
concentrations during long-term anti-TNF therapy in patients with
active rheumatoid arthritis
Popa C et al
During therapy, the changes in disease activity and inflammatory status
were inversely correlated with changes in plasma total and HDL
cholesterol levels and positively correlated with the variation of
atherogenic index.