ESC Congress in Review - Main Edition 2019 - 31

ESC Congress 2019 In Review

Figure 15. Cumulative Incidence of Recurrent Myocardial Infarction, Stroke, need for Urgent Revascularisation, or Cardiovascular Death (MACEplus) in the CANTOS (left) and CIRT (right) Trials
CANTOS

CIRT

Low-dose methotrexate

0.25

Cumalative Incidence (%)

Interleukin-1ß inhibition

MACE+
HR, 0.83
95% CI 0.74-0.92
P = .0006

020
0.15

0.10

0.05
0.0

Follow-up Years

35-40% reductions in IL-6 and hsCRP
17% reduction in CV Events

0.25

MACE+
HR, 0.96
95% CI 0.79-1.16
P = .67

020
0.15

0.10

0.05
0.00

Follow-up Years

No reduction in IL-β, IL-6 nor hsCRP
No reduction in CV Events

CI, confidence interval; CV, cardiovascular; HZ, hazard ratio; IL, interleukin; MACE, major adverse cardiovascular events.
Reprinted from Ridker PM et al. Anti-inflammatory therapy for atherosclerosis: interpreting divergent results from the CANTOS and CIRT clinical trials. J. Intern. Med.
2019;285(5):503-509. Copyright 2019. With permission from John Wiley and Sons.

randomised patients with previous MI or multivessel
coronary artery disease in addition to type 2 diabetes
or metabolic syndrome to low-dose methotrexate (15 to
20 mg) or matching placebo. The trial was halted by the
Data and Safety Monitoring Board after a median of 2.3
years for futility, at which point 4,786 of the 6,158 eligible
patients had been randomised to treatment. More than
60% of patients qualified for the trial with a previous MI.
The data indicated that low-dose methotrexate had
no effect on IL-1β, IL-6, or CRP levels, all markers of
inflammation. In terms of the original primary endpoint,
the use of methotrexate did not reduce the risk of nonfatal MI, non-fatal stroke, or cardiovascular death (HR,
1.01; 95% CI, 0.82 to 1.25; P = .91), effectively eliminating
it as an inexpensive option for treating residual inflammatory risk among patients receiving background statin
therapy (Figure 15) [Ridker PM et al. N Engl J Med 2019].
In January 2018, the primary endpoint was expanded to
include hospitalisation for unstable angina that led to
urgent revascularisation. The purpose of the expanded
endpoint was to provide greater statistical power with
a smaller overall sample size. However, even with the
expanded endpoint, the trial was stopped for futility (HR,
0.96; 95% CI, 0.79 to 1.16; P = .67). There was no treatment effect on any of the secondary endpoints.
The CIRT data suggests that the mechanism of lowdose methotrexate, likely mediated through adenosine
signalling, comprises an entirely different pathway for
inflammation inhibition that is less relevant for atherothrombosis. Therefore, these 2 contemporary trials - 1 positive and 1 informative but with neutral result
- highlight the different relevance of inflammatory
pathways on cardiovascular diseases and guide future

pharmacologic attention away from broad spectrum
anti-inflammatory treatments and towards specific
targeted inhibition upstream (e.g., the NLRP3 inflammasome) or downstream the IL-1/IL-6 pathway of innate
immunity, which is currently tested in clinical trials
(e.g., colchicine is tested in the LoDoCo2, COLCOT, and
CONVINCE). Furthermore, novel emerging novel immunotherapeutic targets are currently considered to become
future therapeutic opportunities for cardiovascular diseases [Lutgens E et al. Eur Heart J 2019]. The independent effects of lipid-lowering and inflammation inhibition
are attractive as combination therapies addressing both
of these atherogenic pathways to provide maximal clinical benefit.
Replay presentation on ESC365

Empagliflozin Induces Effective
Decongestion in Type 2 Diabetes
Patients with ADHF
Written by Michiel Tent

Empagliflozin as add-on therapy can achieve effective
decongestion without increasing the risk of worsening
renal function in patients with type 2 diabetes (T2DM)
with acute decompensated heart failure (ADHF). These
were the results of a randomised study in 38 consecutive
Japanese T2DM patients admitted for ADHF.
Empagliflozin is indicated for the treatment of adults
with insufficiently controlled T2DM as an adjunct to
diet and exercise. The agent has been shown to reduce
the risk of hospitalisation for HF in T2DM patients with
cardiovascular disease. This may be partly explained

Official Peer-Reviewed Highlights From ESC Congress 2019

https://esc365.escardio.org/Congress/ESC-CONGRESS-2019/Tackling-the-inflammatory-side-of-atherosclerosis/185097-clinical-perspective-what-can-we-learn-from-the-cantos-and-cirt-trials

ESC Congress in Review - Main Edition 2019

Table of Contents for the Digital Edition of ESC Congress in Review - Main Edition 2019