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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)
 Appreciate the pathophysiology of CAD in
RA
 Review the recommendations for primary
prevention of CAD in the general
population
 Discuss the application of these
recommendations to patients with
rheumatoid arthritis
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

Arthritis & Rheumatism 2005; 52: 402-411


Results
 Increased risk of
CAD also present
in 2 years prior to
RA diagnosis

 No increased risk
of MI causing
hospitalization

Arthritis & Rheumatism 2005; 52: 402-411


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

Annals of Rheumatic Disease 2005; 64:1595-1601


Results - Women

 No increased risk of cardiovascular admission


Annals of Rheumatic Disease 2005; 64:1595-1601
Results - Men

 No increased risk of cardiovascular admission


Annals of Rheumatic Disease 2005; 64:1595-1601
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 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
 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 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
 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
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

Joint Bone Spine 2006 (in press)


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
Joint Bone Spine 2006 (in press)
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!