coronary artery disease-inflammatory disease hypothesis and respective trials like cantos, colcot, colchicine pci, jupitor ,cirt

1. INFLAMMATION,
ATHEROSCLEROSIS, AND
CORONARY ARTERY DISEASE
Dr Dipak Patade
DMH

2. INFLAMMATION
• Endothelial dysfunction
• oxidative stress in vascular endothelial cells
• macrophage accumulation
• formation of inflammasome
• production of tumor necrosis factor (TNF)-a, IL-1 and IL-6
• Clonal hematopoiesis of indeterminate potential(CHIP)

8. HS-CRP
hsCRP (high-sensitivity C-reactive protein), a marker of systemic inflammation, is clinically
elevated in most healthcare-managed patients with myocardial infarction.
C-reactive protein (CRP) is a member of the pentraxin family of proteins. It is an acute
phase reactant synthesized mainly by the liver.
Serum CRP levels are elevated in response to acute infections, inflammatory conditions
and trauma. In these clinical situations, the serum CRP levels rise rapidly generally
beyond 10 mg/l with a concomitant elevation of erythrocyte sedimentation rates (ESR) .
CRP has a relatively long half-life of 18 to 20 hrs.
stable pentraxin structure.
CRP levels are stable as these do not exhibit diurnal variations or variations in relation
to food intake.
hsCRP is associated with subsequent risk of major adverse cardiovascular events and
death, with associations being linear for hsCRP ranging between 1 and 5 mg/L and
plateauing thereafter to a sustained increased risk.

9. HS-CRP

11. J AM HEART ASSOC. 2019;8:E012638.
DOI: 10.1161/JAHA.119.012638.
• Inflammation, as reflected by hsCRP ≥2 mg/L, was pervasive and present in >60%
of patients.
• Inflammation was particularly common among those with comorbidities and,
notably, among those with low kidney function and anemia.
• the use of statins was associated with lower inflammation risk.
• Inflammation was a strong predictor of subsequent risk of MACEs and death, with
associations being linear for hsCRP ranging between 1 and 5 mg/L and plateauing
thereafter to a sustained increased risk.

12. A Randomized Trial of Rosuvastatin in the Prevention
of Cardiovascular Events Among 17,802 Apparently Healthy
Men and Women With Elevated Levels
of C-Reactive Protein (hsCRP):
The JUPITER Trial

13. HSCRP ADDS PROGNOSTIC INFORMATION BEYOND
TRADITIONAL RISK FACTORS IN ALL MAJOR COHORTS
EVALUATED

14. hsCRP (mg/L)
0
1
2
3
4
5
6
7
8
<0.5 0.5-1.0 1.0-2.0 2.0-3.0 3.0-4.0 4.0-5.0 5.0-10.0 10.0-20.0 >20
WHAT ARE THE ENVIRONMENTAL AND GENETIC INFLUENCES ON CRP?
Relative
Risk of
Future CV
Events
“low risk” “moderate risk” “high risk”

15. WHY CONSIDER STATINS FOR LOW LDL,
HIGH HS-CRP PATIENTS?
Ridker et al, New Engl J Med 2001;344:1959-65

16. WHY CONSIDER STATINS FOR LOW LDL, HIGH HSCRP
PATIENTS?
• In 2001, in an hypothesis generating analysis of apparently healthy individuals in the AFCAPS
/ TexCAPS trial*, it is observed that those with low levels of both LDL and hsCRP had
extremely low vascular event rates and that statin therapy did not reduce events in this
subgroup (N=1,448, HR 1.1, 95% CI 0.56-2.08).
• Thus, a trial of statin therapy in patients with low cholesterol and low hsCRP would not only
be infeasible in terms of power and sample size, but would be highly unlikely to show clinical
benefit.
• In contrast, observations within AFCAPS/TexCAPS that among those with low LDL but high
hsCRP, vascular event rates were just as high as rates among those with overt
hyperlipidemia, and that statin therapy significantly reduced events in this subgroup (N=1,428,
HR 0.6, 95% CI 0.34-0.98).

17. JUPITER
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin
To investigate whether rosuvastatin 20 mg compared to placebo would
decrease the rate of first major cardiovascular events among apparently
healthy men and women with LDL < 130 mg/dL (3.36 mmol/L) who are
nonetheless at increased vascular risk on the basis of an enhanced
inflammatory response, as determined by hsCRP > 2 mg/L.

18. Rosuvastatin 20 mg (N=8901) MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA
JUPITER
Multi-National Randomized Double Blind Placebo Controlled Trial of
Rosuvastatin in the Prevention of Cardiovascular Events
Among Individuals With Low LDL and Elevated hsCRP
4-week
run-in
Ridker et al, Circulation 2003;108:2292-2297.
No Prior CVD or DM
Men >50, Women >60
LDL <130 mg/dL
hsCRP >2 mg/L
JUPITER
Trial Design
Placebo (N=8901)
Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela

19. Follow-Up (years)
0.0 0.5 1.0 1.5 2.0 2.5
0.000.020.040.060.080.10
hsCRP>2
mg/L
hsCRP<2 mg/L
0.0 0.5 1.0 1.5 2.0 2.5
0.000.020.040.060.080.10
CumulativeRateof
RecurrentMyocardialInfarctionorCoronaryDeath(percent)
LDLC>70
mg/dL
LDLC<70
mg/dL
Clinical Relevance of Achieved LDL and Achieved hsCRP
After Treatment with Statin Therapy
Ridker et al NEJM 2005;352:20-28.

20. 0.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.5
0.000.020.040.060.080.100.020.040.060.080.10
Follow-Up (Years)
LDL > 70 mg/dL, CRP > 2 mg/L
LDL < 70 mg/dL, CRP > 2 mg/L
LDL > 70 mg/dL, CRP < 2 mg/L
LDL < 70 mg/dL, CRP < 2 mg/L
Clinical Relevance of Achieved LDL and Achieved hsCRP
AfterTreatment with StatinTherapy
Ridker et al NEJM 2005;352:20-28.

21. JUPITER
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
Placebo 251 / 8901
Rosuvastatin 142 / 8901
0 1 2 3 4
0.000.020.040.060.08
CumulativeIncidence
Number at Risk Follow-up (years)
Rosuvastatin
Placebo
8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157
8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

22. JUPITER
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
Placebo 251 /
8901
Rosuvastatin 142 /
8901
HR 0.56, 95% CI 0.46-0.69
P < 0.00001
Number Needed to Treat (NNT5) = 25
- 44 %
0 1 2 3 4
0.000.020.040.060.08
CumulativeIncidence
Number at Risk Follow-up (years)
Rosuvastatin
Placebo
8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157
8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

23. JUPITER
Secondary Endpoint – All Cause Mortality
Placebo 247 / 8901
Rosuvastatin 198 / 8901
HR 0.80, 95%CI 0.67-0.97
P= 0.02
- 20 %
0 1 2 3 4
0.000.010.020.030.040.050.06
CumulativeIncidence
Number at Risk Follow-up (years)
Rosuvastatin
Placebo
8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 227
8,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246

24. CONCLUSIONS
Among apparently healthy men and women with elevated hsCRP but low LDL,
rosuvastatin reduced by 47 percent incident myocardial infarction, stroke, and
cardiovascular death.
Despite evaluating a population with lipid levels widely considered to be “optimal” in
almost all current prevention algorithms, the relative benefit observed in JUPITER
was greater than in almost all prior statin trials.
In this trial of low LDL/high hsCRP individuals who do not currently qualify for statin
therapy, rosuvastatin significantly reduced all-cause mortality by 20 percent

25. CAN INFLAMMATION REDUCTION, IN THE ABSENCE
OF LIPID LOWERING, REDUCE
CARDIOVASCULAR EVENT RATES?
Ridker ESC 2017

26. Additional
LDL Reduction
IMPROVE-IT : Ezetimibe 6% RRR
FOURIER/SPIRE: PCSK9 Inhibition q2 weeks 15% RRR
Additional
Inflammation Reduction
No Prior Proof ofConcept
Known Cardiovascular Disease
LDL 150 mg/dL (3.8 mmol/L)
hsCRP 4.5mg/L
High Intensity Statin
“Residual Cholesterol Risk”
LDL 110 mg/dL (2.8 mmol/L)
hsCRP 1.8 mg/L
“Residual Inflammatory Risk”
LDL 70 mg/dL (1.8 mmol/L)
hsCRP 3.8 mg/L
RESIDUAL
INFLAMMATORY RISK:
Addressing the Obverse Side of the Atherosclerosis
Prevention Coin
Ridker PM. Eur Heart J 2016;37:1720-22

27. RIDKER PM, ET AL. NEJM 2017; RIDKER PM, ET
AL. THE LANCET 2017
CANTOS
CANakinumab Anti-Inflammatory
Thrombosis Outcomes Study

28. CANTOS
Background and Objective
Inflammation is associated with a higher CV risk, independently of cholesterol levels.
It is not clear whether reducing inflammation, without affecting lipid levels, lowers
the CV risk.
Study objective:
The CANTOS study was designed to assess, whether reducing inflammation in stable
patients with a history of MI and a persistent pro-inflammatory response, leads to a
lower risk of recurrent CV events.
Canakinumab is a fully human monoclonal antibody with anti-inflammatory effects
that has been approved for clinical use in rheumatologic disorders, and reduces
plasma levels of interleukin-6 and high-sensitivity C-reactive protein, without
lowering LDL-c.

29. From CRP to IL-6 to IL-1: Moving
Upstream to Identify Novel Targets for
Atheroprotection
high-affinity human monoclonal anti-human
interleukin-1b (IL-1b) antibody currently indicated
for the treatment of IL-1b driven inflammatory
diseases (Cryopyrin-Associated Period Syndrome
[CAPS], Muckle-Wells Syndrome)
designed to bind to human IL-1b and functionally
neutralize the bioactivity of this pro-inflammatory
cytokine
long half-life (4-8 weeks) with CRP and IL-6
reduction for up to 3 months

30. Median follow up -
3.7 years
Ridker PM, et al. NEJM 2017; Ridker PM, et al. The Lancet 2017

31. Ridker ESC 2017
Canakinumab SC q 3 months
Characteristic Placebo
(N=3347)
50 mg
(N=2170)
150 mg
(N=2284)
300 mg
(N=2263)
Age (years) 61.1 61.1 61.2 61.1
Female (%) 25.9 24.9 25.2 26.8
Current smoker (%) 22.9 24.5 23.4 23.7
Diabetes (%) 39.9 39.4 41.8 39.2
Lipid lowering therapy (%) 93.7 94.0 92.7 93.5
Renin-angiotensin inhibitors (%) 79.8 79.3 79.8 79.6
Prior Revascularization (%) 79.6 80.9 82.2 80.7
LDL cholesterol (mg/dL) 82.8 81.2 82.4 83.5
HDL cholesterol (mg/dL) 44.5 43.7 43.7 44.0
Triglycerides (mg/dL) 139 139 139 138
hsCRP (mg/L) 4.1 4.1 4.2 4.1
CANTOS - BASELINE CLINICAL CHARACTERISTICS

32. Canakinumab SC q 3 months
Placebo
(N=3347)
50 mg
(N=2170)
150 mg
(N=2284)
300 mg
(N=2263)
P-trend
Primary Endpoint
Incidence rate per 100 person-
yr (no. of patients)
HR 95%CI
P value
4.5(535) 4.1(313)
0.80-1.07
0.30
3.86( 320)
0.74-0.98
0.021*
3.9(322)
0.75-0.99
0.031
0.020
Secondary Endpoint
Incidence rate per 100 person-yr
(no. of patients)
HR 95%CI
P value
5.1(601) 4.6(344)
0.78-1.03
0.11
4.3(352)
0.73-0.95
0.005*
4.3(348)
0.72-0.94
0.004
0.003
*Statistically significant, adjusted for multiplicity, in accordance with the pre-specified closed-testing procedures
CANTOS: PRIMARY CLINICAL OUTCOME EFFECTS ON MACE AND
MACE +
Ridker ESC 2017

33. MAIN CV EFFICACY RESULTS: PRIMARY
ENDPOINT
Canakinumab 150/300 led to a significant reduction in hs-CRP and the primary endpoint (non-fatal
MI, non-fatal stroke, CV death) compared with placebo, without affecting LDL-c levels.
The benefit was greatest in patients achieving hs-CRP of 1.8 mg/L after 3 months, with a 27%
RRR for MACE (HR: 0.73; 95%CI: ; P=0.0001).

34. 10
0
-10
-20
-30
-40
-50
-60
-70
PercentChangefromBaseline(median)
hsCRPLDLCHDLCTG
0 3 6 12 24 36 48
10
0
-10
10
0
-10
10
0
-10
Placebo Canakinumab50 Canakinumab150 Canakinumab300
9
Ridker ESC 2017
CANTOS: Dose-Dependent Effects on Inflammatory Biomarkers and Lipids (48 Months)
Placebo SC q 3 mth
Canakinumab 50mg SC q 3 mth
Canakinumab 150mg SC q 3 mth
Canakinumab 300mg SC q 3 mth
Months

35. MAIN NON-CV RESULTS
• Canakinumab 300 mg led to a 67% RRR in incident lung cancer and to a 77% RRR
in fatal lung cancer, compared with placebo
• More leukopenia was seen with canakinumab (0.30, 0.37 and 0.52 per 100 person
years (PY) of exposure for 50, 150 and 300 mg respectively) as compared with
placebo (0.24 per 100 PY, P for trend=0.002).
• Fatal infections were seen more often with canakinumab versus placebo (0.27 for 50
mg, 0.28 for 150 mg, and 0.30 for 300 mg vs per 100 PY, P for trend=0.09, P=0.02 for
combined doses vs. placebo
.Ridker PM, et al. NEJM 2017; Ridker PM, et al. The Lancet 2017

36. CONCLUSIONS
• Canakinumab significantly reduced high-sensitivity C-reactive protein levels from
baseline, as compared with placebo, without reducing the LDL-c levels, and the 150/300
mg doses resulted in a significantly lower incidence of recurrent CV events compared
with placebo.
• The benefit was greatest in patients achieving hs-CRP of 1.8 mg/L after 3 months, with a
27% RRR for MACE.
• The main adverse events were neutropenia and an increase in the risk of fatal infections.
• Additionally, canakinumab 300 mg led to a 51% RRR in death from any cancer, a 67%
RRR in incident lung cancer, and a 77% RRR in fatal lung cancer, compared with
placebo.

37. COLCHICINE CARDIOVASCULAR OUTCOMES TRIAL –
COLCOT

38. COLCOT
The goal of the trial was : evaluate colchicine compared with placebo administered within
30 days of a myocardial infarction.
Study Design
• Randomized
• Parallel
• Double-blind
across 167 sites in 12 countries.

39. COLCOT
• Patients who suffered a myocardial infarction within the last 30 days were randomized to
colchicine 0.5 mg daily (n = 2,366) versus placebo (n = 2,379).
• Total number of enrollees: 4,745
• Duration of follow-up: median 22.6 months
• Mean patient age: 61 years
• Percentage female: 20%
• Percentage with diabetes: 20%
• 93% underwent percutaneous coronary intervention for their index myocardial infarction
• Mean time from myocardial infarction to randomization was 13.5 days

40. COLCOT
Inclusion criteria:
Myocardial infarction within the last 30 days and completion of all intended coronary
revascularization
Exclusion criteria:
• Type 2 myocardial infarction
• Severe left ventricular systolic dysfunction or heart failure
• Stroke within the last 3 months
• Coronary artery bypass surgery within the last 3 years
• Cancer within the last 3 years
• History of inflammatory bowel disease or chronic diarrhea, neuromuscular disease, significant
hepatic or renal disease, drug or alcohol abuse, glucocorticoid therapy, or sensitivity to colchicine

41. COLCOT
The primary efficacy outcome:
• cardiovascular death, myocardial infarction, stroke, resuscitated cardiac arrest, or urgent
hospitalization for unstable angina leading to revascularization
• 5.5% of the colchicine group compared with 7.1% of the placebo group (p = 0.02).
Secondary outcomes:
• Cardiovascular death: 0.8% of the colchicine group compared with 1.0% of the placebo group (p =
nonsignificant)
• Stroke: 0.2% of the colchicine group compared with 0.8% of the placebo group (p < 0.05)
• Urgent hospitalization for unstable angina leading to revascularization: 1.1% of the colchicine group
compared with 2.1% of the placebo group (p < 0.05)
• Infection: 2.2% of the colchicine group compared with 1.6% of the placebo group (p = 0.15)
• Diarrhea: 9.7% of the colchicine group compared with 8.9% of the placebo group (p = 0.35)

48. SUMMARY
• These data underscore the potential of colchicine as an efficient and critically
needed therapy for reducing inflammation post-myocardial infarction to improve
patient cardiovascular outcomes.

49. LIKELY MECHANISM

50. • Effects of Acute Colchicine Administration Prior to Percutaneous
Coronary Intervention: The COLCHICINE-PCI Randomized Trial

51. COLCHICINE-PCI
• investigator-initiated , single-site ,prospective randomized double blind study
• the first to evaluate the effects of an acute pre-procedural administration of colchicine versus
placebo on markers of myocardial injury and inflammation in patients undergoing PCI
• Hypothesis: pre-procedural oral administration of 1.8 mg of colchicine reduces biomarker evidence
of PCI-related inflammation and myocardial injury when compared with placebo
• Population-Adults with suspected ischemic heart disease or acute coronary syndromes referred for
clinically-indicated coronary angiography with possible PCI .
• Key exclusion criteria -
1. Use of oral steroids or NSAIDs •
2. New high-intensity statin
3. GFR
4. Use of strong CYP3A4/P-glycoprotein inhibitor • Use of colchicine

52. COLCHICINE-PCI

53. COLCHICINE-PCI
Primary outcome
• PCI-related myocardial injury (Universal Definition)
• Normal baseline cardiac biomarker: Troponin I above the upper reference limit (URL) •
Elevated baseline cardiac biomarker but falling: Increase in Troponin I by >20%
Key secondary outcomes
• Composite of death from any cause, non-fatal myocardial infarction (MI), or target vessel
revascularization at 30 days
• Non-fatal MI was defined as type 1 or type 4a (Tn >5x URL) MI per the Universal
Definition
• PCI-related MI as defined by the Society for Cardiovascular Angiography and
Interventions (Tn >70x URL)

54. COLCHICINE-PCI
• Inhibits neutrophil chemotaxis and activity in response to vascular injury
• Inhibits inflammasome signaling and reduces the production of active IL-1β
• Reduces neutrophil-platelet interaction and aggregation
• The standard regimen of colchicine used for gout flares (1.2 mg PO followed by 0.6
mg PO administered over an hour) has rapid onset of anti-inflammatory effects

55. INFLAMMATORY BIOMARKER SUBSTUDY
ENDPOINTS
Primary endpoint
• Between group difference in the change in plasma IL-6 concentration from baseline
to 1 hour post-PCI
Secondary endpoints
• Change in plasma IL-6 concentration from baseline to 6 and 24 hours post PCI
• Change in plasma IL-1β concentration from baseline to 1, 6, and 24 hours post-PCI
• Change in hsCRP concentration from baseline to 24 hours post-PCI

56. COLCHICINE-PCI

57. COLCHICINE-PCI

58. COLCHICINE-PCI

59. COLCHICINE-PCI

60. COLCHICINE-PCI

61. COLCHICINE-PCI

62. COLCHICINE-PCI

63. COLCHICINE-PCI

64. COLCHICINE-PCI

65. COLCHICINE-PCI

66. SUMMARY
• This investigator-initiated, single-site prospective randomized double blind study is the
first to evaluate the effects of an acute pre-procedural administration of colchicine versus
placebo on markers of myocardial injury and inflammation in patients undergoing PCI •
• Compared with placebo, short-term pre-procedural colchicine: •Did not reduce PCI-
related myocardial injury or MACE at 30 days
• Did attenuate PCI-related increase in IL-6 and hsCRP concentration at 24 hours post-
PCI
• • This is the first study to demonstrate that an oral load of colchicine prevents a rise of
inflammatory biomarkers in acute injury.

67. A Randomized, Double-Blind, Placebo-
Controlled Trial of Low-Dose Methotrexate
for the Prevention of Atherosclerotic Events

68. CIRT HYPOTHESIS

76. CONCLUSIONS
• Taken together, the CANTOS and CIRT trials demonstrate that-
• inflammation inhibition can significantly reduce cardiovascular event rates
independent of lipid-lowering and blood pressure reduction.
• However, at least at this point in development, given the positive findings of
CANTOS and the neutral findings of CIRT, inhibition of the IL-1b to IL-6 to CRP
pathway of innate immunity appears to be important for atheroprotection.
• These two trials - CANTOS positive, CIRT a neutral control - thus point directly
toward future work targeting upstream inhibition of the NLRP3 inflammasome or
downstream inhibition of IL-6 as potential targets for novel cardiovascular
therapeutics.

77. CONCLUSIONS
COLCOT trial demonstrates that
colchicine might be someday join the "standard five drug cocktail" after a myocardial
infarction of aspirin, dual antiplatelet therapy, a statin, an angiotensin-converting
enzyme inhibitor, and a β-blocker !!!!!