Coronary Artery Disease In Rheumatoid Arthritis
A Focus On Primary Prevention
Dr. Irfan Dhalla
(PGY3, Internal Medicine)
Rheumatology Rounds June 27, 2006
Objectives
Understand
the epidemiologic relationship between coronary artery disease (CAD) and rheumatoid arthritis (RA) the pathophysiology of CAD in RA
Appreciate
Review
the recommendations for primary prevention of CAD in the general population the application of these recommendations to patients with rheumatoid arthritis
Discuss
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 3
Should we recommend ASA to this patient?
Question
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 artery disease is the leading cause of death among patients with RA of unrecognized myocardial infarction or sudden cardiac death is about twice normal in patients with RA
Coronary
Risk
Arthritis & Rheumatism 2005; 52: 402-411
Study Design
Incidence
cohort of individuals with RA in Rochester, Minnesota, from 1955-95 randomly selected after matching for age, sex and length of medical history CAD events before and after diagnosis of RA
Arthritis & Rheumatism 2005; 52: 402-411
Controls
Examined
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 cohort was local population
Comparison
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
Understand
the epidemiologic relationship between coronary artery disease (CAD) and rheumatoid arthritis (RA) the pathophysiology of CAD in
RA
Appreciate
Review
the recommendations for primary prevention of CAD in the general population the application of this evidence to patients with rheumatoid arthritis
Discuss
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
Understand
the epidemiologic relationship between coronary artery disease (CAD) and rheumatoid arthritis (RA) the pathophysiology of CAD in
RA
Appreciate
Review
the recommendations for primary prevention of CAD in the general population the application of this evidence to patients with rheumatoid arthritis
Discuss
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 – risk 1020% over 10 years – risk > 20% over 10 years (or DM or established CAD)
Intermediate High
ACC/AHA Recommendations
Stop Eat
smoking
better depression 30 minutes per day
Treat
Exercise
Aim
for normal weight (BMI 18.5 – 24.9)
Use
non-pharmacologic measures to aim for BP < 120/80
ACC/AHA Recommendations for ASA and Statins
ASA
High risk Intermediate risk Low risk Yes
Statins
Aim for LDL < 2.5 (new: or LDL < 2.0)
Consider Aim for LDL < 3.5 (new: or LDL < 2.5) No Aim for LDL < 4.5 (new: LDL < 3.5 if risk factors present)
Objectives
Understand
the epidemiologic relationship between coronary artery disease (CAD) and rheumatoid arthritis (RA) the pathophysiology of CAD in RA
Appreciate
Review
the recommendations for primary prevention of CAD in the general population the application of these recommendations to patients with rheumatoid arthritis
Discuss
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-centre
double-blind RCT of atorvastatin 40 mg od vs. placebo
met 1987 ACR criteria and had active disease
No limitation on disease duration Active disease defined as 6 swollen joints plus two of
Patients
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
ESR
– decreased by 0.53 – decreased by 6.94 mm/hr joints – decreased by 1.5 joints – decreased by 2.2
Tender
Swollen
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
Primary
prevention guidelines do not consider inflammation/RA as a risk factor for CAD
may be more beneficial when inflammation present
Aspirin
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
Attention
should be given to CV risk in patients with RA RA should be counted as a cardiovascular risk factor in the determination of eligibility for statins 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)
Active
RA
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) 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
Cons
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!