Received: 3 May 2019 Revised: 22 July 2019 Accepted: 30 July 2019

DOI: 10.1002/clc.23246

CLINICAL INVESTIGATIONS

Interleukin-1 blockade treatment decreasing

cardiovascular risk

Zi-Heng Zheng1† | Xun Zeng1,2† | Xiao-Ying Nie1,2† | Yun-Jiu Cheng1 | Jun Liu1 |
Xiao-Xiong Lin1 | Hao Yao1 | Cheng-Cheng Ji1 | Xu-Miao Chen1 | Fan Jun1 |
Su-Hua Wu1

1
Department of Cardiology, The First Affiliated
Hospital, Sun Yat-Sen University and Key Abstract
Laboratory on Assisted Circulation, NHC, Background: Interleukin-1 (IL-1) played a role in the occurrence and development of
Guangzhou, China
2 atherosclerosis and cardiovascular events. However, the association between IL-1
Outpatient Department, The First Affiliated
Hospital, Sun Yat-Sen University, Guangzhou, blockage treatment and reducing of cardiovascular risk remains poorly defined.
China
Hypothesis: IL-1 blockage treatment reduce the risk and incidence rate of overall
Correspondence major adverse cardiovascular events (MACE), all-cause death, acute myocardial
Su-Hua Wu, Department of Cardiology, the
infarction(MI), unstable angina and heart failure.
First Affiliated Hospital, Sun Yat-Sen
University and Key Laboratory on Assisted Methods: We performed a search of published reports by using MEDLINE database
Circulation, NHC, NO. 58 Zhongshan Rd II,
(January 1, 2005 to April 1, 2018). The randomized controlled trials (RCTs) that
Guangzhou 510080, China.
Email: [email protected] reported sample size and occurrence numbers in test group and placebo group for
the associations of interest were included.
Funding information
Guangzhou City Science and Technology Results: Eight RCT studies involving 15 647 participants were identified. Compared
Program, Grant/Award Number:
with those who took no IL-1 blockage, patients taking IL-1 blockage experienced a
201508020057; National Natural Science
Foundation of China, Grant/Award Number: decreased risk of overall MACE (RR 0.88, 95% CI 0.82-0.94), unstable angina
81370285
(RR 0.80, 95% CI 0.66-0.98), and breakthrough or recurrence of heart failure
(RR 0.44, 95% CI 0.22-0.87). No association was found between IL-1 blockage treat-
ment and death from all cause (RR 0.91, 95% CI 0.83-1.00) as well as acute MI (RR
0.85, 95% CI 0.71-1.01). The RRs associated with overall MACE, death from all cause,
acute MI, and unstable angina for anakinra were 1.05, 1.16, 2.97, and 0.56, respec-
tively, and for canakinumab were 1.05, 0.91, 0.80, and 0.80, respectively.
Conclusions: Administration of IL-1 blockage was associated with decrease risks of
overall MACE, unstable angina, and breakthrough or recurrence of heart failure, but
not with death from all cause as well as acute MI.

KEYWORDS
anakinra, canakinumab, cardiovascular events, Interleukin-1 blockade, meta-analysis

†
Zi-Heng Zheng, Xun Zeng, and Xiao-Ying Nie contributed equally to this study.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.

942 wileyonlinelibrary.com/journal/clc Clinical Cardiology. 2019;42:942–951.

ZHENG ET AL. 943

1 | I N T RO D UC T I O N 2 | METHODS

A chronic low-grade inflammatory reaction as an important role in The meta-analysis was conducted following the PRISMA guidelines
the pathophysiological procedure in the occurrence and develop- (Text S1). We performed a systematic search of relevant studies publi-
ment of atherosclerosis and cardiovascular diseases is now largely shed from January 1, 2005 to April 1, 2018 in the MEDLINE data-
1,2 bases with no restrictions.
accepted. Anti-inflammatory therapy provided a new treatment
strategy in some cardiovascular diseases and the secondary preven-
tion of cardiovascular events.3,4 There are many inflammatory fac- 2.1 | Search Strategy
tors that mediate the process of chronic inflammation. IL-1 is well
known as one of the main members of the inflammatory factor The following text and key words in combination: “IL-1β Inhibition”

family. The process of inflammation mediated by IL-1 can cause and “Atherosclerosis,” “cardiovascular,” “myocardial infarction,” “Acute

many kinds of diseases. 5-7

Long-term chronic inflammation can lead coronary syndrome,” “ACS,” “stroke”; “IL-1 block” and “Acute coronary
syndrome,” “Atherosclerosis,” “cardiovascular,” “ACS,” “stroke,” “myo-
to the formation of arterial plaques as well as atherogenesis,8 and
cardial infarction”; “IL-1 inhibition” and “ACS,” “cardiovascular,”
active inflammatory process may trigger the rupture of plaque
“stroke,” “Acute coronary syndrome,” “myocardial infarction,” “Athero-
which increasing the risk of coronary thrombosis, then leading to
sclerosis”; “canakinumab” and “ACS,” “Acute coronary syndrome,”
clinical ischemic events.9
“Atherosclerosis,” cardiovascular,” “myocardial infarction,” “stroke,”
There are four IL-1 blockers available now, anakinra, can-
10-13 “diabetes”; “anakinra” and “ACS,” “Acute coronary syndrome,”
akinumab, rilonacept, and gevokizumab. Anakinra is the main
“Atherosclerosis,” “cardiovascular,” “myocardial infarction,” “stroke,”
kind of IL-1 blocker. It is a recombinant human IL-1 receptor
“diabetes” were used to search for studies published from January
antagonist that competitively inhibit IL-1b and IL-1a by binding the
1, 2005 to April 1, 2018 in the MEDLINE databases. We manually
IL-1 receptor type I. A number of clinical studies are reported
checked the reference list of each retrieved report to identify other
about anakinra used in the treatment of rheumatoid arthritis and
relevant studies in order to identify any studies that were not identi-
approved its effectiveness.11-13 It was also studies in used of
14 15 16 fied from the preliminary searches.
adult-onset Still, gout, Behçet's disease, and other autoim-
mune diseases. In an animal experiment with mouse model of AMI,
anakinra was given before the surgical induction of 2.2 | Study Selection
Ischemia/reperfusion. The study showed that compared with mice
The following methodological restrictions were imposed for the inclu-
in vehicle-treated group the mice in anakinra prophylactic treat-
sion criteria to minimize differences between studies: (1) Published in
ment group had higher LVEF and less infarct size.17 It approved
the English language with research method of randomized controlled
the function of protection of myocardium and preservation of car-
trials (RCTs), published as original articles. (2) The subjects must have
diac function using anakinra treatment before the onset of AMI.
the basis of cardiovascular disease or cardiovascular complications of
Other animal experiments were also launched confirming the car-
other diseases can cause cardiovascular disease. (3) The studies must
diovascular effectiveness of anakinra.18,19 Clinical trials about ana-
present the sample size, occurrence number and nonoccurrence num-
kinra's effectiveness on reducing cardiovascular risk and
ber both in test group and placebo group of each relevant end point.
cardiovascular events have also been developed. Canakinumab is a
In instances of multiple publications, the most up to date or compre-
human monoclonal anti-human IL-1b antibody that can significantly
hensive information was used.
lower the level of CRP.20 Cryopyrin-associated periodic syndromes,
a series of IL-1b driven inflammatory disorders, have been con-
firmed that could be induced rapid and sustained remission of 2.3 | Data Abstraction
20-22
symptoms by using canakinumab. Other clinical trials also have From each retrieved report, we extracted the following data: name of
been launched to confirm the effectiveness on treatment with can- the lead investigator, year of publication, country where the study
akinumab in arthritis, diabetes, and gout patients, and have been was performed, methods for assessment of end points, main investi-
shown to lower CRP levels.23-25 There have been only a few publi- gational drug the study use, the sample size of the study including
shed studies of canakinumab in patients with coronary artery dis- total sample size as well as sample size of test group and placebo
ease. Its effectiveness on cardiovascular diseases still needs more group, average age of test group and placebo group, proportions of
further researches. men and women of test group and placebo group, Body Mass
Given these backgrounds, we conducted a meta-analysis to sum- Index(BMI) of test group and placebo group, proportions of hyperten-
marize all published RCT studies to examine whether IL-1 blockage sion patients of test group and placebo group, proportions of diabetes
treatment reduce the risk and incidence rate of overall major adverse patients of test group and placebo group, mean and mean's 95% Con-
cardiovascular events, all-cause death, acute myocardial infarction, fidence Interval (CI) of C Reactive Protein (CRP) on the baseline of
unstable angina and heart failure. test group and placebo group, end point of each study.
944 ZHENG ET AL.

2.4 | Statistical Analysis 458 studies were excluded because they were not RCTs. In 68 RCTs
with abstract review, there were 51 not-relevant studies or duplicated
We used Relative Risk (RR) for the measure of the association
studies. Then we read the full review of remaining 17 studies for
between IL-1 blockage treatment and cardiovascular risk. Heteroge-
detailed reading. However, four studies were excluded as not includ-
neity among studies was formally assessed using Q and I2 statistics
ing or not all cardiovascular patients, one was excluded as cross-over
applying the following interpretation for Q and I2: P > .1 = low hetero-
study, one was excluded as not finding full review, two were excluded
geneity, P < .1 = high heterogeneity; I2<50% = low heterogeneity,
as results not published yet, one was excluded as cannot be combined
40% < I2 < 60% = moderate heterogeneity, I2>60% = high heteroge-
for change rates of CRP. The leaving eight studies were finally
neity. Fixed-effects models were used for estimating pooled RRs if
included in the meta-analysis.
heterogeneity among studies was permissible (both P > .1 and
I2 < 40%). When there was biggish heterogeneity among studies
(P < .1 or I2 > 40%), random rather than fixed effects models was used 3.2 | Study Characteristics
in order to take into account the heterogeneity. Subgroup analyses,
A total of 15 647 individuals were included in eight studies, in
meta-regression models and sensitivity analysis would be carried out
which 74.6% were male. The year of publication of these studies
to investigate potential sources of between-study heterogeneity if
ranged from 2010 to 2017. Of those eight studies, eight studied
there was high heterogeneity among studies. Publication bias was
tested using funnel plot and Egger's regression test. We used STATA, for drug of anakinra and three for canakinumab. All eight studies

version 14.0 (Stata Corp LP, College Station, TX) for all analyses. Two- evaluated the end points of overall major adverse cardiovascular

sided P values <.05 were considered statistically significant. events and death from any cause with Interleukin-1 blockade
treatment, seven studies evaluated the end points of acute myo-
cardial Infarction, six studies evaluated the end points of unstable
3 | RESULTS angina, five studies evaluated the end points of breakthrough or
recurrence of heart failure. The detailed data of age, body mass
3.1 | Study Selection
index (BMI), proportion of hypertension, proportion of diabetes,
The results of the search were shown in Figure 1. Five-hundreds and and baseline of patient's C reactive protein (CRP) are showed in
twenty-six studies were reviewed in preliminary search. Of these Table 1.

F I G U R E 1 Flowchart of the selection of

studies included in meta-analysis
 ZHENG ET AL.

TABLE 1 Characteristics of the included eight RCTs

No. of Article 1 2 3 4 5 6 7 8
First author Benjamin W. Allison C. Morton Antonio Abbate Antonio Abbate Antonio Abbate Robin P. Choudhury P.M. Ridker P.M. Ridker
Van Tassell
Year 2017 2014 2010 2013 2015 2016 2017 2017
Region America UK America America America Canada,UK,America, 39 Countries 39 Countries
Germany and Israel
Trial type RCT RCT RCT RCT RCT RCT RCT RCT
Drug Anakinra Anakinra Anakinra Anakinra Anakinra Canakinumab Canakinumab Canakinumab
Case(n[P/T]) 34(18/16) 182(89/93) 10(5/5) 30(15/15) 40(20/20) 189(94/95) 5628 9534(3182/6352)
(3344/2284)
Age (P/T) 61(56-68)/ 61.3(12.3)/61.4(11.7) 51.8(28-65)/ 58.2(35-83)/ 58(51-65)/ 61.9(6.9)/61.7(7.8) 61.1(10.0)/ 61.0(54.0-68.0)/61.0
57(53-66) 45.4(34-59) 59.1(46-86) 57(48-60) 61.2(10.0) (55.0-68.0)(T1);
61.0(54.0-68.0)(T2)
Male (n[%]) (P/T) 13(72)/12(75) 67(75.3)/63(67.7) 5(100)/3(60) 13(86.7)/9(60.0) 18(90)/12(60) 80(85)/82(86) 2479(74.1)/ 2365(74)/4735(75)
1709(74.8)
BMI(kg/㎡) 30(27-38)/ 28.4(4.7)/30.0(7.1) NA NA NA 30.3(4.0)/30.3(4.1) NA 29.7(26.6-33.9)/
36(29-41) 30.5(27.0-34.7)
(T1);29.6(26.4-33.1)(T2)
Hypertestion NA 29(32.6)/31 (33.3) 3(60)/5(100) 11(73.3)/7(46.7) 14 (70)/12(60) 83(88)/81(85) 2644(79.1)/ 2514(79)/5075(80)
(%) (P/T) 1814(79.4)
Diabetes(%)(P/T) 12(67)/9(56) 8(9.0)/15(16.1) 1(20)/2(40) 3(20.0)/3(20.0) 4(20)/5(25) 81(86)/81(85) 1333(39.9)/ 1265(40)/2536(40)
1814(79.4)
CRP([mg/L])(P/T) 5.2(2.0-11.9)/ 5.21(3.75, 7.22)/ NA 4.3(2.2-7.5)/ NA 1.85(0.83-3.88)/ 4.10(2.75-6.85)/ 4.10(2.75–6.85)/5.55
7.2(3.3-12.3) 5.38(4.12, 7.04) 7.0(2.3-8.7) 1.77(0.84-3.74) 4.25(2.85-7.05) (3.60-9.25)(T1);
3.40(2.45-5.20)(T2)
End point All MACE All MACE All MACE All MACE All MACE All MACE All MACE All MACE
ALL death ALL death ALL death ALL death ALL death ALL death ALL death ALL death
AMI AMI AMI AMI AMI AMI AMI
UA UA UA UA UA UA
HF HF HF HF HF

Abbreviations: AMI, acute myocardial infarction; AUC, area under curve; BMI, body-mass index; CRP, C reactive protein; HF, heart failure; LVESVi, left ventricular end systolic volume index; MACE, major
adverse cardiovascular event; NA, not available; P, placebo group; RCT, randomized controlled trial; T, test group; T1, test group1; T2, test group2; UA, unstable angina.
945
946 ZHENG ET AL.

FIGURE 2 Interleukin-1 Blockade treatment and Cardiovascular Risk. The dotted line in the forest plot represents fixed-effects summary risk
estimate

3.3 | Association with overall major adverse 3.4 | Association with death from all cause
cardiovascular events
Eight studies reported the outcome of death from all cause with
Eight studies reported the outcome of overall major adverse cardio- 15 467 participants and 1566 events (Figure 2). Overall, using of
vascular events with 15 467 participants and 2809 events (Figure 2). Interleukin-1 blockade treatment was associated with no decreased
Overall, using of Interleukin-1 blockade treatment was associated with or increased risk of death from all cause (RR 0.91, 95% CI 0.83-1.00)
a decreased risk of overall major adverse cardiovascular events with low between-study heterogeneity using fixed-effects model (I2:
(RR 0.88, 95% CI 0.82-0.94) with low between-study heterogeneity 0.0%, P = .825) (Figure 2 and 3). Neither funnel plots (Supplement
using fixed-effects model (I2: 37.3%, P = .131) (Figures 2 and 3). Neither Figure 1) nor Egger and Begg tests showed evidence of publication
funnel plots (Supplement Figure 1) nor Egger and Begg tests showed bias (Egger, P = .645; Begg, P = 1.000).
evidence of publication bias (Egger, P = .763; Begg, P = 1.000). In subgroup analysis by investigational drug, using of anakinra
In subgroup analysis by investigational drug, using of anakinra showed no association with a decreased or increased risk of death
shows no association with a decreased or increased risk of overall from all cause (RR 1.16, 95% CI 0.40-3.40) with low between-study
major adverse cardiovascular events (RR 1.05, 95% CI 0.68-1.61) with heterogeneity using fixed-effects model (I2: 0.0%, P = .575) while
2
high between-study heterogeneity using fixed-effects model (I : using of canakinumab also shows no association with a decreased or
60.0%, P = .041) while using of canakinumab shows the association increased risk of death from all cause (RR 0.91, 95% CI 0.82-1.00)
with a decrease risk of overall major adverse cardiovascular events with low between-study heterogeneity using fixed-effects model (I2:
(RR 0.87. 95% CI 0.81-0.94) with low between-study heterogeneity 0.0%, P = .712) (Figure 4).
using fixed-effects model (I2: 0.0%, P = .582) (Figure 4). To explore
study heterogeneity between studies of using anakinra, we used the
3.5 | Association with acute myocardial infraction
random-effects model instead of model showing little of risk estimation
(RR 0.89, 95% CI 0.41-1.90) and between-study heterogeneity (I2: There were seven studies reporting the outcome of acute myocardial
60.0%, P = .041). There was a larger sample study that is opposite to infraction with 6113 participants and 472 events (Figure 2). Overall,
the result direction (RR 3.35, 95% CI 1.15-9.79) (Figure 4). To further using of Interleukin-1 blockade treatment was associated with no
explore study heterogeneity, a sensitivity analysis was done to remov- decreased or increased risk of acute myocardial infraction (RR 0.85,
ing this larger sample study with the abnormal result. After removing 95% CI 0.71-1.01) with low between-study heterogeneity using fixed-
this study, the result of meta-analysis with the remaining studies also effects model (I2: 18.4%, P = .289) (Figures 2 and 3). However, funnel
showing no association with risk of overall major adverse cardiovascu- plots (Supplement Figure 1) and Egger tests showed there was the
lar events (RR 0.68, 95% CI 0.42-1.11) but with low between-study evidence of publication bias (Egger, P = .014). We used trim and fill
2
heterogeneity using fixed-effects model (I : 20.2%, P = .289). method for test publication bias. The result showed that there were
ZHENG ET AL. 947

F I G U R E 3 Forest plot showing relative risks of overall major adverse cardiovascular events, death from any cause, acute myocardial
Infarction, unstable angina and breakthrough or recurrence of heart failure. The size of each square is proportional to the study's weight (inverse
of variance). The dotted line in the forest plot represents fixed-effects summary risk estimate

three studies defecting after four iterations. The pooled effect after In subgroup analysis by investigational drug, using of anakinra
trimming and filling (OR 0.88, 95% CI 0.70-1.06) did not change showed the association with an increased risk of acute myocardial
largely compared with the pooled effect before trimming and filling infraction (RR 2.97, 95% CI 1.11-7.93) with low between-study
(OR 0.842, 95% CI 0.662-1.022). In addition, result of test for hetero- heterogeneity using fixed-effects model (I2: 0.0%, P = .931) while
2
geneity also did not change (I : 23.81% before trimming and filling as using of canakinumab shows the association with a decreased risk
well as I2: 32.19% after trimming and filling). Although there is publi- of acute myocardial infraction (RR 0.80, 95% CI 0.67-0.97) with
cation bias, the result is steady. low between-study heterogeneity using fixed-effects model (I2:
948 ZHENG ET AL.

F I G U R E 4 Forest plot showing result of by subgroup analysis by investigational drug about relative risks of overall major adverse
cardiovascular events, death from any cause, acute myocardial Infarction, unstable angina. The size of each square is proportional to the study's
weight (inverse of variance). The dotted line in the forest plot represents fixed-effects summary risk estimate

0.0%, P = .456) using fixed-effects model (I2: 0.0%, P = .712) of unstable angina (RR 0.80, 95% CI 0.66-0.98) with low between-
(Figure 4). study heterogeneity using fixed-effects model (I2: 0.0%, P = .819)
(Figures 2 and 3). Neither funnel plots (Supplement Figure 1) nor
Egger and Begg tests showed evidence of publication bias (Egger,
3.6 | Association with unstable angina
P = .979; Begg, P = .734).
There were six studies reporting the outcome of unstable angina with In subgroup analysis by investigational drug, using of anakinra
5931 participants and 460 events (Figure 2). Overall, using of showed no association with an increased or decreased risk of unstable
Interleukin-1 blockade treatment was associated with a decreased risk angina (RR 0.56, 95% CI 0.13-2.37) with low between-study
ZHENG ET AL. 949

heterogeneity using fixed-effects model (I2: 0.0%, P = .692) while effectiveness of interleukin-1 blocker used in treatment in diabetes.
using of canakinumab shows the association with a decreased risk of And significant decrease in CRP level could also be observed in
unstable angina (RR 0.80, 95% CI 0.67-0.97) with low between-study these studies.30-32 Interleukin-1 blockers may also decrease cardio-
heterogeneity using fixed-effects model (I2: 0.0%, P = .456) using vascular risk by reducing related diseases that can cause cardiovas-
fixed-effects model (I2: 0.0%, P = .819) (Figure 4). cular events, but further studies are still warranted to confirm this
presumption.
In the present meta-analysis, we found that there was no signifi-
3.7 | Association with breakthrough or recurrence of
heart failure cant association between interleukin-1 blockade treatment and death
from all cause as well as acute myocardial infraction. The one of rea-
Five studies reported the outcome of breakthrough or recurrence of sons may be that Infection is a common adverse reaction of
heart failure with 303participants and 31 events (Figure 2). Overall, interleukin-1 blockers. Compared with canakinumab, anakinra has the
using of Interleukin-1 blockade treatment was associated with a higher risk of Infection owing to inhibit both L-1b and IL-1a, especially
decreased risk of breakthrough or recurrence of heart failure in patients using immunosuppressive agents at the same time. Clinical
(RR 0.44, 95% CI 0.22-0.87) with low between-study heterogeneity studies showed that although the increase of infection-related deaths
using fixed-effects model (I2: 13.6%, P = .327) (Figures 2 and 3). Nei- was not observed, using anakinra has been associated with an
ther funnel plots (Supplement Figure 1) nor Egger and Begg tests increase in serious infections in patients who were also receiving
showed evidence of publication bias (Egger, P = .244; Begg, other immunomodulating agents.13,33 Second, patients taking
P = 1.000). interleukin-1 blockers might be sicker and have other related diseases
In subgroup analysis by investigational drug, using of anakinra like diabetes or gout comparing with patients not taking interleukin-1
shows the association with a decreased risk of outcome of break- blockers, which can increase the risk of patients' death. Therefore,
through or recurrence of heart failure (RR 0.44, 95% CI 0.21-0.88) long-term survival effect after interleukin-1 blockade treatment still
with low between-study heterogeneity using fixed-effects model (I2: needs further clinical studies.
35.5%, P = .199) (Figure 4). There were some limitations to this meta-analysis. First, when
we evaluated the association between anakinra and overall major

3.8 | Association with CRP adverse cardiovascular events, we found there was high between-
study heterogeneity. Sensitivity analysis showed that heterogeneity
In this meta-analysis, we also extracted the available CRP data in main came from a larger sample study with an opposite result direc-
included studies and have done a simple analysis to evaluate the asso- tion. Second, there was publication bias when evaluating the associ-
ciation between interleukin-1 blockade treatment and level of CRP. ation with acute myocardial infraction, although trimming and filling
The result showed that using of Interleukin-1 blockade treatment was showed the result was still steady. Third, the relatively small num-
associated with a significantly decreased level of CRP (SMD -0.30, ber of studies limited our ability to compare the risk for reported
95% CI –0.51 to –0.09) with low between-study heterogeneity using events between different investigational drugs, especially can-
fixed-effects model (I2: 0.0%, P = .545) (Figure 4). akinumab. Fourth, some studies with big sample size and some with
small sample size, these big sample size studies showed a greater

4 | DISCUSSION impact on the trend of results.

Strengths of this study included small between-studies heteroge-

The present meta-analysis showed that administration of interleukin- neity, long durations of follow-up and all well-established clinical

1 blockers was associated with decrease risks of overall major adverse RCTs. In addition, our pooled estimates were based on detailed

cardiovascular events, unstable angina, and breakthrough or recur- adjustment for confounding variables.

rence of heart failure.

The possible mechanism that interleukin-1 blockade treatment 5 | C O N CL U S I O N S
decreased the risk of cardiovascular events was that it reduced the
inflammatory response thereby decreasing the production of inflam- In conclusion, the results from our meta-analysis of clinical RCTs
matory mediators, especially the CRP. CRP as a widely used as suggested thatinterleukin-1 blockade treatment was associated
inflammatory marker in clinical settings, it is also has been recog- with decrease risk of overall major adverse cardiovascular events,
nized as an independent predictor of adverse cardiovascular unstable angina, and breakthrough or recurrence of heart failure,
events.26 Many studies have reported that the level of CRP is but not with death from all cause as well as acute myocardial
closely related to the occurrence of adverse cardiovascular infraction. Future clinical and experimental studies should focus on
27-29
events. The result of this meta-analysis showed that in the understanding the exact mechanisms and risk between interleukin-
patients using interleukin-1 blockade treatment, the level of CRP 1 mediated inflammation and cardiovascular events. In addition,
has been significantly decreased. Several studies have reported the large well-designed RCTs to further evaluate interleukin-1
950 ZHENG ET AL.

blockers' safety and stability of cardiovascular effect are also still evidence from the OMEGA trial. J Rheumatol. 2008;35(8):1538-
needed. 1544.
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S.H.W. conceived and designed the experiments. Z.H.Z., X.Z., X.Y.N.,
1012.
Y.J.C., J.L., X.X.L., H.Y., C.C.J., X.M.C., and J.F. performed the experi- 14. Hong D, Yang Z, Han S, Liang X, Ma K. Interleukin 1 inhibition with
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J.F. analyzed the data. Z.H.Z., X.Z., X.Y.N., Y.J.C., J.L., X.X.L., H.Y., safety. Drug des Devel Ther. 2014;8:2345-2357.
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tis Res Ther. 2007;9(2):R28.
Z.H.Z., X.Z., and X.Y.N. wrote the first draft of the manuscript. Z.H.Z., 16. Grayson PC, Merideth M, Sen HN, et al. Treatment of mucocutane-
S.H.W., X.Z., X.Y.N. contributed to the writing of the manuscript. ous manifestations in Behçet's disease with anakinra: a pilot open-
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