Coronary Artery Disease in Rheumatoid Arthritis

Coronary Artery Disease In
Rheumatoid Arthritis
A Focus On Primary Prevention
Dr. Irfan Dhalla

(PGY3, Internal Medicine)
Rheumatology Rounds
June 27, 2006
Objectives
 Understandthe epidemiologic relationship
between coronary artery disease (CAD)
and rheumatoid arthritis (RA)
 Appreciate the pathophysiology of CAD in
RA
 Reviewthe recommendations for primary
prevention of CAD in the general
population
 Discuss
the application of these
recommendations to patients with
rheumatoid arthritis
Case – G.T.
 59F
 Longstanding rheumatoid arthritis

 Was on Methotrexate and Plaquenil
 Methotrexate recently discontinued because of
solitary lymph node enlargement
 Arthritis flaring
 Not exercising
 Finds it difficult to do chores around the house
 Other illnesses
 Hypertension, hypothyroidism
Case – G.T.
 Current medications
 Hydroxychloroquine, candesartan,
levothyroxine, alendronate, vitamin D
 Not using NSAIDs
 Physical examination
 BP 135/85
 MSK – 10 swollen joints (both wrists, 4 MCPs,
2 MTPs and 2 PIPs), most with stress pain
 Laboratory investigations
 LDL 3.3, HDL 1.09, TC 5.49, TG 0.6
Case – G.T.
 Question 1
Should this patient be referred for a stress
test?
 Question 2
Should we recommend ASA to this patient?
 Question 3
Should we recommend a statin to this
patient?
Objectives
 Understand the epidemiologic relationship
between coronary artery disease (CAD) and
rheumatoid arthritis (RA)
RA
 Review the recommendations for primary
population
 Discuss the application of these
Epidemiology of CAD in RA
 Life
expectancy for individuals with
RA is (probably) reduced
 Coronary artery disease is the
leading cause of death among
patients with RA
 Riskof unrecognized myocardial
infarction or sudden cardiac death is
about twice normal in patients with
RA
Arthritis & Rheumatism 2005; 52: 402-411
Study Design
 Incidencecohort of individuals
with RA in Rochester, Minnesota,
from 1955-95
 Controlsrandomly selected after
matching for age, sex and length of
medical history
 Examined CAD events before and
after diagnosis of RA

Results
 Increased risk of
CAD also present
in 2 years prior to
RA diagnosis
 No increased risk
of MI causing
hospitalization

Annals of Rheumatic Disease 2005; 64:1595-1601
Study Design
 Inception
cohort of 1010 RA patients in
Stockport, England
 Comparison cohort was local population

 Adjusted for age and sex only
 Examined cardiovascular admissions

and mortality

Results - Women
 No increased risk of cardiovascular admission

Results - Men
 No increased risk of cardiovascular admission

Objectives
RA
population
 Discuss the application of this evidence to
patients with rheumatoid arthritis
Inflammation is a hallmark
of atherosclerosis
Leukocyte Recruitment and Diapedesis
Nature 2002; 420; 868-874

Role Of T-cell In Atherogenesis
Nature 2002; 420; 868-874

Role Of The Mast Cell
In Atherogenesis
Nature 2002; 420; 868-874

Life History Of An Atheroma
Nature 2002; 420; 868-874

Inflammation in RA  CAD
Circulation 2003; 108: 2957-63

Postulated Mechanisms
For Increased CAD In RA
 Cytokines (TNF-α, IL-1β, IL-6) have effects on many
tissues
 TNF-α worsens insulin sensitivity in muscle
 IL-6 and TNF-α stimulate adipocyte lipolysis 
increased free fatty acids
 Dyslipidemia (low HDL, high TG, smaller, denser LDL
than in non-RA) is atherogenic
 Endothelial cell dysfunction with increased leukocyte
adhesion molecules
 Increased clotting potential (fibrinogen, vWF, platelet
levels elevated)
Circulation 2003; 108: 2957-63
Objectives
RA
population
 Discuss the application of this evidence to
patients with rheumatoid arthritis
Primary Prevention Of CAD
In The General Population
 Step 1: Calculate 10 year
risk using Framingham
score
 Low – risk of CAD < 10%
over 10 years
 Intermediate
– risk 10-
20% over 10 years
 High– risk > 20% over
10 years (or DM or
established CAD)
ACC/AHA Recommendations
 Stop smoking
 Eat better
 Treat depression
 Exercise 30 minutes per day
 Aim for normal weight (BMI 18.5 – 24.9)
 Usenon-pharmacologic measures to
aim for BP < 120/80
ACC/AHA Recommendations
for ASA and Statins
ASA Statins
High risk Yes Aim for LDL < 2.5
(new: or LDL < 2.0)
Intermediate Consider Aim for LDL < 3.5
risk (new: or LDL < 2.5)
Low risk No Aim for LDL < 4.5
(new: LDL < 3.5 if risk
factors present)
Objectives
between coronary artery disease (CAD) and
rheumatoid arthritis (RA)
RA
prevention of CAD in the general population
 Discuss
the application of these
The Problem
 Framingham risk calculators and

AHA/ACC guidelines do not account
for inflammation
NEJM 1997; 336: 973-979
Study Design
 Sub-study of Physicians Health Study,
a 2 x 2 RCT of aspirin and beta-
carotene to prevent CAD and cancer in
healthy physicians
 Main
study showed 44% reduction in
CAD events with aspirin
 trial terminated early
 Post-hoc analysis stratifying by CRP
level to assess role of inflammation
NEJM 1997; 336: 973-979

Subjects Were Quite Healthy
NEJM 1997; 336: 973-979

ASA More Effective In Those With High CRP
NEJM 1997; 336: 973-979

Statins May Have A
Dual Role In RA
Lancet 2004; 363: 2015-21

Study Design
 Single-centredouble-blind RCT of
atorvastatin 40 mg od vs. placebo
 Patientsmet 1987 ACR criteria and had
active disease
 No limitation on disease duration
 Active disease defined as 6 swollen joints plus
two of
 6 tender joints
 ESR > 28
 morning stiffness > 30 minutes
Lancet 2004; 363: 2015-21

Study Design
 Exclusions
 Met criteria for statin
 On prednisone > 10 mg/d
 Elevated LFTs, CK
 Primary outcome: change in DAS28

 Secondary outcomes: changes in CRP,
ICAM-1, lipids, thrombotic markers
Lancet 2004; 363: 2015-21

Results
Baseline
Characteristics
Lancet 2004; 363: 2015-21

Results – Baseline Characteristics
Lancet 2004; 363: 2015-21

Results – After 6 Months Of Treatment
Lancet 2004; 363: 2015-21

Results – After 6 Months Of Treatment
Statins Compared To Placebo
 DAS – decreased by 0.53
 ESR – decreased by 6.94 mm/hr
 Tender joints – decreased by 1.5
 Swollen joints – decreased by 2.2
 LDL decreased by 1.33 mmol/L
 Fibrinogen,
plasma viscosity, ICAM-1, IL-6
also decreased
Lancet 2004; 363: 2015-21

Three Additional Factors to Consider
When Applying CAD Primary
Prevention Guidelines to RA Patients
 Primaryprevention guidelines do not

consider inflammation/RA as a risk factor
for CAD
 Aspirin
may be more beneficial when
inflammation present
 Statins may have a disease-modifying
effect in RA
Are there guidelines for managing
CAD risk in patients with RA?
Recommendations for CVD in RA
Joint Bone Spine 2006 (in press)

Guideline Development Process
 Setting: France
 12 expert rheumatologists developed
questions to be addressed
 4 rheumatologists reviewed the literature
 94 expert rheumatologists attended
workshops and voted on suggested answers

Selected Recommendations
 Attentionshould be given to CV risk
in patients with RA
 Active
RA should be counted as a
cardiovascular risk factor in the
determination of eligibility for statins
 RA by itself does not indicate aspirin
for primary prevention. When used,
attention should be paid to GI side
effects if NSAIDs are also being used
Back To The Case
 59F with RA
 Longstanding RA, disease still active
 Hypertension controlled with medications
 LDL 3.3, HDL 1.1, TC 5.5, TG 0.64
 Framingham risk calculation

 10 year risk: 3% (low risk)
 But it would be 12% (intermediate risk) if a male had
the same history
 Should we adjust this risk given that she has

RA?
Question 1:
Should She Have A Stress Test?
 No evidence or guidelines
 Pros
 Would help us know if there is flow-limiting stenosis
 Would identify left main or triple-vessel disease if
present (survival benefit with intervention)
 Cons
 Plaque rupture does not necessarily occur at the site
of a flow-limiting stenosis
 If positive, would need angiogram and/or bypass
surgery – and would be exposed to significant risk
complications
 My vote: Would not recommend
Question 2:
Should We Recommend ASA?
 Pros
 Potentially reduce risk of MI, stroke
 Side effect profile well known
 Cons
 May be at higher risk of GI bleeding if using
NSAIDS
 My
vote: Would not recommend. (But
would recommend for a male patient.)
Question 3:
Should We Recommend Statins?
 Pros
 May reduce risk of MI, stroke
 May reduce RA disease activity
 Cons
 Risk of significant adverse effects very low, especially if
CK & ALT/AST monitored
 My vote: Would not recommend, but would

view treatment as very reasonable, and would
definitely recommend treatment to a male in
this scenario.
Summary and Conclusions
 Risk of CAD elevated in patients with RA
 Use Framingham score to estimate risk, then
consider adjusting upwards for presence of
RA
 Limited evidence regarding use of ASA and
statins in patients with RA
 More evidence needed
 In the meantime, must rely on imperfect
evidence, clinical judgment and patient
preference
Questions?
Thank you!

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Coronary Artery Disease In

Dr. Irfan Dhalla

 Longstanding rheumatoid arthritis

Arthritis & Rheumatism 2005; 52: 402-411

Arthritis & Rheumatism 2005; 52: 402-411

 Comparison cohort was local population

 Examined cardiovascular admissions

Annals of Rheumatic Disease 2005; 64:1595-1601

 No increased risk of cardiovascular admission

 No increased risk of cardiovascular admission

Nature 2002; 420; 868-874

Nature 2002; 420; 868-874

Nature 2002; 420; 868-874

Nature 2002; 420; 868-874

Circulation 2003; 108: 2957-63

 Framingham risk calculators and

NEJM 1997; 336: 973-979

NEJM 1997; 336: 973-979

NEJM 1997; 336: 973-979

Lancet 2004; 363: 2015-21

Lancet 2004; 363: 2015-21

 Primary outcome: change in DAS28

Lancet 2004; 363: 2015-21

Lancet 2004; 363: 2015-21

Lancet 2004; 363: 2015-21

Lancet 2004; 363: 2015-21

Lancet 2004; 363: 2015-21

 Primaryprevention guidelines do not

Joint Bone Spine 2006 (in press)

Joint Bone Spine 2006 (in press)

 Framingham risk calculation

 Should we adjust this risk given that she has

 My vote: Would not recommend, but would

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