Transcript Slide 1

The Cardiovascular Inflammation Reduction Trial (CIRT)
Scientific Rationale and Trial Overview
Slide Set for Investigators
Paul M Ridker, MD
Eugene Braunwald Professor of Medicine
Harvard Medical School
Director, Center for Cardiovascular Disease Prevention
Brigham and Women’s Hospital, Boston MA
Cardiovascular Inflammation Reduction Trial (CIRT)
What is CIRT?
CIRT is an NHLBI-funded randomized double-blind placebo-controlled trial designed to:
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directly test the inflammatory hypothesis of atherothrombosis
determine whether the common anti-inflammatory drug low-dose
methotrexate (LDM, target dose of 15 to 20 mg po weekly) will
reduce rates of recurrent myocardial infarction, stroke, or
cardiovascular death among patients with a prior history of
myocardial infarction and either type 2 diabetes or metabolic
syndrome
determine whether LDM will reduce the rate of new onset type 2
diabetes among those with metabolic syndrome at study entry
N = 7,000 NHLBI-Sponsored
Enrollment to Start March 2013
350 - 400 US and Canadian Sites
Cardiovascular Inflammation Reduction Trial (CIRT)
Why is the NHLBI funding CIRT?
Like rheumatoid arthritis and psoriasis [two inflammatory disorders successfully
treated with low-dose methotrexate (LDM)], atherothrombosis is an inflammatory
disease. Yet, to date, no clinical trial has been completed that addresses whether
inhibiting inflammation may reduce cardiovascular event rates.
Cardiovascular Inflammation Reduction Trial (CIRT)
hsCRP, a clinical biomarker of inflammation, is commonly
used as a method to predict cardiovascular risk
Risk of future heart attack
Risk of future stroke
P Trend <0.001
P Trend <0.01
Relative Risk of Stroke
Relative Risk of MI
3
2
1
0
1
2
3
4
Quartile of hsCRP
Ridker et al, N Engl J Med 1997;336:973–979.
2
1
0
1
2
3
4
Quartile of hsCRP
4
Cardiovascular Inflammation Reduction Trial (CIRT)
Inflammation as a predictor of future heart attack and stroke
Meta-analysis of 54 Prospective Cohort Studies
Inflammation and risk of future cardiovascular events: 2010
Risk ratio (95% CI)
Coronary Heart Disease
All Vascular Deaths
3.0
2.5
3.0
2.5
2.0
2.0
1.5
1.5
1.0
1.0
0.5
1.0
2.0
4.0
8.0
0.5
1.0
hsCRP concentration (mg/L)
Emerging Risk Factor Collaborators, Lancet January 2010
2.0
4.0
8.0
Cardiovascular Inflammation Reduction Trial (CIRT)
Meta-analysis of 54 Prospective Cohort Studies
The magnitude of independent risk associated with inflammation is at least as large,
if not larger, than that of BP and cholesterol. However, in contrast to BP and cholesterol,
no clinical trials have been completed to see if lowering inflammation
can lower cardiac event rates.
Risk Ratio (95%CI)
hsCRP
1.37 (1.27-1.48)
Systolic BP
1.35 (1.25-1.45)
Total cholesterol
1.16 (1.06-1.28)
Non-HDLC
1.28 (1.16-1.40)
0.5
1.0
1.2
1.4
1.8
Risk Ratio (95%CI) per 1-SD higher usual values
Adjusted for age, gender, smoking, diabetes, BMI, triglycerides, alcohol, lipid levels, and hsCRP
Emerging Risk Factor Collaborators, Lancet January 2010
CR-6
Cardiovascular Inflammation Reduction Trial (CIRT)
hsCRP, TC, and HDLC in 166,596 Individuals
The incremental value to risk prediction (ie the change in C-statistic) is virtually
identical for hsCRP as for TC and HDLC, both of which are universally measured
in all global risk prediction models.
.0043 .0050
.0039
Non-lipid risk factors
plus TC
plus TC plus HDLC
plus TC plus HDLC plus hsCRP
0.0
0.01
0.02
Change in C-statistic
(as compared with non-lipid-based model)
Emerging Risk Factor Collaborators, NEJM 2012;367:1310-1320
Cardiovascular Inflammation Reduction Trial (CIRT)
Translation to clinical practice: The Reynolds Risk Score
www.reynoldsriskscore.org
Reynolds
Risk
Score
Age
Smoking
SBP
TC
HDLC
hsCRP
Family
History
HbA1c
hsCRP (mg/L)
is not
CRP (mg/dL)
Cardiovascular Inflammation Reduction Trial (CIRT)
The fundamental question
Can Targeted Anti-Inflammatory
Therapy Reduce Cardiovascular
Event Rates and Prolong Life?
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Cardiovascular Inflammation Reduction Trial (CIRT)
Design considerations
Stable CAD (post MI)
On Statin, ACE/ARB, BB, ASA
Persistent Evidence of Inflammation
How to define?
DM or MetSyn
What
agent
to study?
Anti-Inflammatory
Intervention
Placebo
Low Dose
Methotrexate
Nonfatal MI, Nonfatal Stroke, Cardiovascular Death
Ridker P. Thromb Haemost 2009
Cardiovascular Inflammation Reduction Trial (CIRT)
Why low-dose methotrexate?
I. Extensive clinical experience and well-known safety profile
Low Dose Methotrexate (15 to 20 mg po weekly + folic acid)
Used weekly by millions of Americans and Canadians as first line
therapy for rheumatoid arthritis and psoriasis.
Enviable safety record with over 40 years of use among older
individuals with similar co-morbidities as those who have suffered a
prior heart attack.
Inexpensive and widely used, unlikely to have any unknown off-target
effects.
Guidelines for safe use already exist and are strictly followed in the
CIRT protocol and in its inclusion and exclusion criteria.
Cardiovascular Inflammation Reduction Trial (CIRT)
Why Low Dose Methotrexate (LDM)?
II. Observational evidence strongly suggests a reduction in vascular events
Cohort
Group
HR* (95 % CI)
Endpoint
Exposure
Wichita
Choi 2002
RA
0.4 (0.2 - 0.8)
0.3 (0.2 - 0.7)
0.4 (0.3 – 0.8)
Total Mortality
CV Mortality
CV Mortality
LDM
LDM
LDM < 15 mg/wk
Netherlands
van Helm 2006
RA
0.3
0.2
0.2
0.2
(0.1 – 0.7)
(0.1 – 0.5)
(0.1 – 1.2)
(0.1 – 0.5)
CVD
CVD
CVD
CVD
LDM only
LDM + SSZ
LDM + HCQ
LDM + SSZ + HCQ
Miami VA
Pradanovich 2005
PsA
0.7
0.5
0.8
0.6
(0.6 – 0.9)
(0.3 – 0.8)
(0.7 – 1.0)
(0.5 – 0.8)
CVD
CVD
CVD
CVD
LDM
LDM < 15 mg/wk
LDM
LDM < 15 mg/wk
RA
CORRONA
Solomon 2008
RA
0.6 (0.3 – 1.2)
0.4 (0.2 – 0.8)
CVD
CVD
LDM
TNF-inhibitor
QUEST-RA
Narango 2008
RA
0.85 (0.8 – 0.9)
0.82 (0.7 – 0.9)
MI
0.89 (0.8 - 1.0)
Stroke
CVD
LDM
UK Norfolk
2008
RA,
LDM
LDM
PsA
0.6 (0.4 – 1.0)
Total Mortality
0.5 (0.3 – 1.1)
CV Mortality
LDM
LDM
Cardiovascular Inflammation Reduction Trial (CIRT)
Overall Design and Primary Aim
Stable CAD (post MI)
On Statin, ACE/ARB, BB, ASA
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Persistent Evidence of Inflammation
Diabetes or Metabolic Syndrome
LDM 15-20 mg po
once weekly
+ daily folate
LDM placebo po
once weekly
+ daily folate
Nonfatal MI, Nonfatal Stroke,
Cardiovascular Death
To directly test the
inflammatory hypothesis of
atherothrombosis.
To evaluate in a
randomized, double-blind,
placebo-controlled trial
whether LDM given at a
target dose of 15 to 20 mg
po weekly will reduce rates
of recurrent myocardial
infarction, stroke, or
cardiovascular death among
patients with a prior history
of myocardial infarction and
either type 2 diabetes or
metabolic syndrome.
N = 7,000 NHLBI-Sponsored
Enrollment to Start March 2013
350 US and Canadian Sites
Cardiovascular Inflammation Reduction Trial (CIRT)
Secondary Aims
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To determine in a randomized, double-blind, placebo-controlled
trial whether LDM will reduce rates of:
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all-cause mortality
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hospitalization for unstable angina
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incident congestive heart failure
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deep vein thrombosis and/or pulmonary embolism
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percutaneous revascularization or coronary artery bypass
procedures
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atrial fibrillation
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new onset diabetes among those with metabolic syndrome but
not diabetes at study entry
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progression of peripheral vascular disease
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aortic stenosis
Cardiovascular Inflammation Reduction Trial (CIRT)
Study Population and Basic Inclusion Criteria
• CIRT will include approximately 7,000 men and women
– aged 18 years and over
– have suffered a documented myocardial infarction in
the past five years
– have completed any planned coronary
revascularization procedures associated with the
qualifying event
– have been on a stable secondary prevention regimen
for a minimum of 60 days
– have either type 2 diabetes or metabolic syndrome
– no contraindication to LDM
Cardiovascular Inflammation Reduction Trial (CIRT)
Exclusion Criteria – I. Contraindications to Methotrexate
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Chronic infectious disease
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tuberculosis
severe fungal disease
chronic hepatitis B or C
known HIV infection
Renal insufficiency
Interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis
Non-basal cell malignancy or treated lymphoproliferative disease
within the past 5 years
Abnormal baseline blood counts or LFTs
History of alcohol abuse or unwillingness to limit alcohol
consumption to less than 4 drinks weekly
Women of child bearing potential or those intending to breastfeed
Class IV heart failure
Cardiovascular Inflammation Reduction Trial (CIRT)
Exclusion Criteria – II. Concomitant Medications
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Requirement for use of drugs that alter folate metabolism
(trimethoprim/sulfamethoxazol) or reduce tubular excretion
(probenecid) or known allergies to antibiotics making avoidance of
trimethoprim impossible
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Currently taking methotrexate, oral steroids, or other
immunosuppressive or biologic response modifiers
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Eligible study participants will be encouraged to have up to date
pneumococcal and influenza vaccinations as recommended
based on their age and underlying medical conditions
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All of these inclusion and exclusion criteria are consistent with or
more conservative than those recommended by the American
College of Rheumatology for the use of methotrexate in
rheumatoid arthritis or psoriasis
Cardiovascular Inflammation Reduction Trial (CIRT)
LDM Complications Will Be Minimized
• Regular monitoring of liver function and hematologic
indices using a centralized methodology designed to
ensure participant safety, allow for dose reductions while
maintaining the study blind, and provide an efficient
method to address issues of compliance and follow-up
on a cost-effective centralized basis.
• All dose adjustments will be made centrally following
simple clinical algorithms
• Medical monitors with methorexate expertise available at
all times
• Study drug will be dispensed in child-safe monthly
calendar packs to improve safety and compliance
Cardiovascular Inflammation Reduction Trial (CIRT)
theCIRT.org website
For More Information or to Obtain Study Forms
Please Call (855) 437-9330
or visit
theCIRT.org