Novel insights targeting inflammation in CVD: the LoDoCo 2 trial - - PowerPoint PPT Presentation

Novel insights targeting inflammation in CVD: the LoDoCo 2 trial

Jan Hein Cornel, MD, PhD Professor of Cardiology Alkmaar, The Netherlands Nijmegen, The Netherlands

Grant from ZonMw and Dutch heart foundation.

Disclosures

Further LDL-C lowering reduces CV-risk

… Large residual burden …

7-year event rates

CV, cardiovascular; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction Cannon, et al. N Engl J Med 2015;372:2387-97

Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization (≥30 days), or stroke

30 20 Event Rate (%) 10 40 6 5 4 3 T ime since randomization (years) Residual C V

• risk

2 1 7 HR 0.936 p=0.016 Simva 34.7% 2742 events

Simvastatin Simvastatin– ezetimibe

Atherosclerosis: non-resolving inflammation

Libby et al, Nature 2011

Residual risk

Lawler et al, Eur Heart J 2020 [ahead of print]

How common is residual inflammatory risk?

PROVE-IT

29% 13% 14% 44%

IMPROVE- IT

33% 14% 14% 39%

Residual Inflammatory Risk hsCRP > 2 mg/L LDLC < 70 mg/dL Residual Cholesterol Risk hsCRP < 2 mg/L LDLC > 70 mg/dL Both hsCRP > 2 mg/L LDLC > 70 mg/dL Neither hsCRP < 2 mg/L LDLC < 70 mg/dL

• Ridker. Circulation Res 2017;120:617-9

• Libby. IL-1b as a Target for Therapy JACC 2017;70:2278–89

Ridker et al., EHJ 2019

Different anti-inflammatory therapies

Ridker et al., NEJM 2017. Ridker et al., NEJM 2018.

The inflammatory process in atherosclerosis is primarily driven by the formation of cholesterol crystals (CCs) within atheroma

Atherosclerosis is a crystallopathy

Nidorf et.al. Viewing atherosclerosis through a crystal lens https://doi.org/10.1016/j.jacl.2020.07.003

Janoudi et al. European Heart Journal (2016) 37, 1959–1967

Mulay et al. N Engl J Med 2016;374:2465-76.

Riksen & Netea, Mol Aspects Med 2020

Metabolic – Epigenetic crosstalk

The Low Dose Colchicine (LoDoCo) trials

Jan Hein Cornel

Dit project wordt mogelijk gemaakt door:

Herfsttijloos (Colchicum autumnale)

• used by the ancient Greeks and Egyptians
• broad cellular effects that include inhibition of tubulin

polymerization

M1 M 2

Cor e Core

F Ost Macro CCs Micro CCs

Circulating Leucocytes

S

C3b

IL-1β Expression CC Clearance IL 10, TGFβ

Endothelial Disruption Endothelial Disruption

S 1 2 6 5 3 Cholesterol Crystals Activate Complement Inflammatory Response Risk of Inflammatory Injury Resolution - Sclerosis Fibro-Calcific Deposition SMC

Athero-thrombosis

4

C5b-9

Colchicine

Proteomic analysis LoDoCo2 (run-in period)

• 176 patients post-ACS patients selected from LoDoCO2 study
• Serum drawn at baseline and after 30 days run-in; all patients treated with

colchicine 0.5mg daily, paired samples

• Olink proteomic analysis: Panels: CV-II and CV-III; 184 serum proteins
• High sensitive C-reactive protein available from previous analysis

Attenuation of inflammasome related proteins

• hsCRP: 1.52 mg/l (IQR 0.66 – 3.43 mg/l) to 1.00 mg/l (IQR 0.37 – 2.28 mg/l, p <0.001)
• Reduction of IL-18 by -4.8%
• NLRP3 inflammasome produced caspase-1 cleaves pro-IL-18 into IL-18
• Reduction of IL-1 receptor antagonist by -8.6%
• Reflects reduced levels of IL-1β, caspase-1 cleaves pro-IL-1β into IL-1β
• Reduction of IL-6 by -9.7%
• Production of IL-6 strongly induced by IL-1
• However:
• Reduction of NF-κB essential modulator, activator of NF-κB, which is necessary for NLRP3

inflammasome activation -> more upstream attenuation?

• Strongest attenuation in proteins not directly related to inflammasome
• More important role for neutrophils?

Conclusions ProLoDoCo analysis

Treatment with colchicine in subjects with chronic CAD resulted in a significant reduction in thirty-seven serum proteins, underscoring a marked anti-inflammatory effect stretching beyond the NLRP3 inflammasome pathway, and suggesting an important role of neutrophil inhibition. The effect of colchicine on the measured circulating proteins is independent of baseline hsCRP levels and largely independent of change in hsCRP levels, which questions the ability of CRP measurements to assess the efficacy of colchicine treatment.

Objective: To determine whether colchicine 0.5mg once daily prevents cardiovascular events in patients with chronic coronary disease. Design: Investigator-initiated, double-blind, placebo-controlled, event-driven trial. Enrolment: Began in Australia (GenesisCare) in August 2014. Expanded to The Netherlands, Dutch Network for Cardiovascular Research (WCN) in October 2016. Last enrolment: November 4, 2018.

Protocol

Patients aged 35 – 82 years with proven coronary disease Clinically stable >6 months

No advanced renal disease, heart failure or severe valvular heart disease

30-day open label run-in of colchicine 0.5mg daily Colchicine Tolerant, clinically stable and willing Placebo Planned to begin close-out 12 months after the last participant had been randomized*

* If 331 primary events had accrued – sufficient to detect a 30% effect of therapy with 90% power

Primary end point

The composite of

Cardiovascular death Myocardial infarction Ischemic stroke Ischemia-driven coronary revascularization

6528 5522

Enrolled

91.3% Tolerated open label therapy

Randomized

Followed for a median of 29 months (12-64 months) 90.3% in each arm continued their trial medication 3.4% in each arm ceased due to perceived effects

Close-out

Began on December 4, 2019; Ended February 17, 2020 99.9% Final, end point status known

5521

5521

Colchicine Placebo

N=2762 N=2760 Age, years 65.8 +8.4 65.9 +8.7 Male 2305 (83.5) 2352 (85.9) Risk Factors and History Current Smoker 318 (11.5) 330 (12.0) Hypertension 1421 (51.4) 1387 (50.3) Diabetes 492 (17.8) 515 (18.7) Prior Revascularization 2419 (83.4) 2468 (84.0) Prior ACS 2323 (84.1) 2335 (84.6)

• Last ACS >24m

1570 (67.6) 1609 (68.9)

Baseline characteristics

Colchicine Placebo

N= 2762 N= 2760

Medication use at baseline

Single anti-platelet therapy 1849(66.9%) 1852(67.1%) Dual anti-platelet therapy 638(23.1%) 642(23.3%) Anticoagulant 342(12.4%) 330(12.0%) Statin 2594(93.9%) 2594(94.0%) Any lipid lowering agent 2670(96.7%) 2665(96.6%) Renin angiotensin inhibitor 1995(72.2%) 1965(71.2%) Beta-blocker 1692(61.3%) 1735(62.9%) Calcium-channel blocker 633(22.9%) 611(22.1%)

Hazard ratio, 0.69 (95% CI, 0.57-0.83), P<0.001 Placebo Colchicine

5 10 15 20 12 24 36 48 60

Months since Randomization Cumulative Incidence (%)

2760 2655 1703 821 590 161 2762 2685 1761 890 629 166

• No. at Risk

Primary end point

Cardiovascular death, Myocardial infarction, Ischemic stroke or Ischemia-driven coronary revascularization

264 placebo vs 187 colchicine

Hazard ratio, 0.72 (95% CI, 0.57-0.92), P=0.007 Placebo Colchicine

5 10 15 20 12 24 36 48 60

Months since Randomization Cumulative Incidence (%)

2760 2694 1760 863 625 174 2762 2714 1787 913 651 176

• No. at Risk

Key secondary end point

Cardiovascular death, Myocardial infarction or Ischemic stroke

157 placebo vs 115 colchicine

Ranked secondary end points

Colchicine (N = 2762) Placebo (N = 2760) Hazard Ratio (95% CI) P Value

• 1. Cardiovascular death, Myocardial infarction,
• r Ischemic stroke

115(4.2) 157(5.7) 0.72(0.57-0.92) 0.007

• 2. Myocardial infarction or Ischemia-driven

coronary revascularization 155(5.6) 224(8.1) 0.67 (0.55-0.83) <0.001

• 3. Cardiovascular death or Myocardial

infarction 100(3.6) 138(5.0) 0.71(0.55-0.92) 0.010

• 4. Ischemia-driven coronary revascularization

135(4.9) 177(6.4) 0.75(0.60-0.94) 0.012

• 5. Myocardial infarction

83(3.0) 116(4.2) 0.70 (0.53-0.93) 0.014

• 6. Ischemic stroke

16(0.6) 24(0.9) 0.66(0.35-1.25) 0.198

• 7. Death from any cause

73(2.6) 60(2.2) 1.21(0.86-1.71)

• 8. Cardiovascular death

20(0.7) 25(0.9) 0.80(0.44-1.44)

Colchicine Placebo

(N = 2762) (N = 2760)

Non-cardiovascular death 53(1.9) 35(1.3) Diagnosis of new cancer 120(4.3) 122(4.4) Hospitalization for infection 137(5.0) 144(5.2) Hospitalization for pneumonia 46(1.7) 55(2.0) Hospitalization for gastro-intestinal reason 53(1.9) 50(1.8)

Serious adverse events

Neutropenia 3(0.1) 3(0.1) Myotoxicity 4(0.1) 3(0.1)

Prespecified sub-groups

Summary

In patients with chronic coronary disease, low-dose colchicine

Reduced the risk of;

• The primary composite end point

Cardiovascular death, myocardial infarction, ischemic stroke or ischemia-driven coronary revascularization.

• Key secondary composite end points

Cardiovascular death, myocardial infarction or ischemic stroke.

• Individual secondary end points

Myocardial infarction & Ischemia-driven coronary revascularization.

… with broadly consistent effects across a range of clinical subgroups

Was well tolerated and appeared safe

The incidence of premature discontinuation & serious adverse events were both low & equivalent to placebo.

Our co-investigators

Tjerk S.J. Opstal, Salem H.K. The, Xiao-Fang Xu, Mark A. Ireland, Timo Lenderink, Donald Latchem, Pieter Hoogslag, Jeroen Schaap, Anastazia Jerzewski, Peter Nierop, Alan Whelan, Randall Hendriks, Henk Swart, Aaf F.M. Kuijper, Maarten W.J. van Hessen, Pradyot Saklani, Isabel Tan, Angus G Thompson, Allison Morton, Chris Judkins, Willem A. Bax, Maurits Dirksen, Marco M.W. Alings, Graeme

• J. Hankey

The trial coordinators

Trial monitors and staff from GenesisCare and the Heart and Vascular Research Institute of Sir Charles Gairdner Hospital Perth WA, including Penny Buczec, Denny Craig, Karen Doherty, Louise Nidorf, and Karen Youl, and from the Dutch Network for Cardiovascular Research (WCN), including Marjelle van Leeuwen as project manager, Ingrid Groenenberg and Glentino Rodriguez for data management, Erik Stroes, Max Silvis, & Tim de Vries for medical review, Petra Bunschoten & Wendy Tousain for site monitoring

Organizational support

The National Health Medical Research Council of Australia, The Sir Charles Gairdner Research Advisory Committee Grant, The Withering Foundation The Netherlands, The Netherlands Heart Foundation, The Netherlands Organization for Health Research and Development, and The Dutch Pharma consortium; Teva, Disphar and Tiofarma. Both the active and placebo tablets were supplied at no cost by; Tiofarma in The Netherlands and Aspen Pharmacare in Australia

Neither the funders nor pharma had any role in the design

• f the study, the collection or management of the data, the

statistical analyses, or presentation of the results

We would like to acknowledge

Every participant in the trial

an investigator-initiated trial, of an old drug in an ancient disease

Research Publication

“ Authors Name” Article Name JOURNAL NAME , Volume XX, Issue XX, Date , Page Ref https://doi.org/XXX/yyj/zzzz