Anti-Inflammatory Therapy with Canakinumab for the ...CANTOS randomized 10,061 patients with prior myocardial infarction and hsCRP ≥ 2 mg/L to canakinumab 50 mg, 150 mg, 300 mg,

10.1161/CIRCULATIONAHA.118.038010

1

Anti-Inflammatory Therapy with Canakinumab for the Prevention of

Hospitalization for Heart Failure

Running Title: Everett et al.; Canakinumab for Heart Failure Prevention

Brendan M. Everett, MD, MPH1,2; Jan H. Cornel, MD, PhD3; Mitja Lainscak, MD4;

Stefan D. Anker, MD, PhD5; Antonio Abbate, MD, PhD6; Tom Thuren, MD7; Peter Libby, MD1;

Robert J. Glynn, ScD2; Paul M. Ridker, MD, MPH1,2

1The Division of Cardiovascular Medicine; 2The Division of Preventive Medicine, Brigham and

Women’s Hospital, Harvard Medical School, Boston, MA; 3Department of Cardiology,

Noordwest Ziekenhuisgroep, Alkmaar, Netherlands; 4Division of Cardiology, General Hospital

Murska Sobota, Slovenia and Faculty of Medicine, University of Ljubljana, Slovenia;

5Department of Cardiology (CVK) and Berlin-Brandenburg Center for Regenerative Therapies

(BCRT); German Centre for Cardiovascular Research (DZHK) partner site Berlin; Charité

Universitätsmedizin Berlin, Germany ; 6Pauley Heart Center, Virginia Commonwealth

University, Richmond, VA; 7Novartis, East Hanover, NJ & Basel, Switzerland.

Address for Correspondence:

Brendan M. Everett, MD, MPH

900 Commonwealth Ave

Boston, MA 02215

Tel: 857-307-1990

Fax: 617-232-3541

Email: [email protected]

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Abstract

Background: Subclinical inflammation associates with an increased risk of heart failure, and

with adverse prognosis in patients with established heart failure. Yet, treatments specifically

directed at reducing inflammation in patients with heart failure have not yet shown improved

clinical outcomes. We tested the hypothesis that the IL-1 inhibitor canakinumab would prevent

hospitalization for heart failure (HHF) and the composite of HHF or heart failure-related

mortality.

Methods: We randomized 10,061 patients with prior myocardial infarction (MI) and high-

sensitivity C-reactive protein (hsCRP) ≥ 2 mg/L to canakinumab 50 mg, 150 mg, 300 mg, or

placebo, given subcutaneously once every three months. In total, 2,173 (22%) reported a history

of heart failure at baseline. We tested the hypothesis that canakinumab prevents prospectively

collected (HHF) events and the composite of HHF or heart failure-related mortality.

Results: A total of 385 patients had a HHF event during a median follow up of 3.7 years.

Patients who had HHF were older, had higher body mass index, and were more likely to have

diabetes, hypertension, and prior coronary bypass surgery. As anticipated, median (Q1, Q3)

baseline concentrations of hsCRP were higher among those who had HHF during follow up than

those who did not [5.7 mg/L (3.5, 9.9) vs. 4.2 mg/L (2.8, 6.9), respectively, P<0.0001]. The

unadjusted hazard ratios (95% CI) for HHF with each dose of canakinumab compared to placebo

were 1.04 (0.79-1.36) for 50 mg, 0.86 (0.65-1.13) for 150 mg, and 0.76 (0.57-1.01) for 300 mg

(P-trend = 0.025). The composite of HHF or HF-related mortality was also reduced by

canakinumab, with unadjusted hazard ratios (95% CI) of 1.00 (0.78-1.30) for 50 mg, 0.87 (0.67-

1.12) for 150 mg, and 0.78 (0.60-1.01) for 300 mg (P-trend=0.037).

Conclusions: These randomized, double-blind, placebo-controlled data suggest that therapy with

canakinumab, an IL-1 inhibitor, is related to a dose-dependent reduction in hospitalization for

heart failure and the composite of hospitalization for heart failure or heart failure-related

mortality in a population of patients with prior MI and elevations in hsCRP.

Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT01327846

Key Words: Inflammation; heart failure; clinical trials

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Clinical Perspective

What is new?

• Subclinical inflammation is known to associate with an increased risk of heart failure,

and with a worse prognosis for those with established heart failure.

• In this study, a randomized, placebo-controlled trial of the monoclonal antibody to

interleukin-1 beta canakinumab, we found a dose-dependent reduction in the risk of

hospitalization for heart failure among those randomly allocated to active therapy.

• This study represents the first time a targeted anti-inflammatory therapy has reduced

hospitalization for heart failure in at-risk patients with a history of myocardial infarction

and ongoing subclinical inflammation.

What are the clinical implications?

• The results presented here are exploratory and hypothesis-generating, but nonetheless

represent the first large-scale evidence indicating that IL-1 targeted therapy may have a

role in preventing hospitalization for heart failure and heart-failure related mortality.

• IL-1 beta inhibition offers a mechanistically distinct and novel approach to treating heart

failure and may offer benefits to patients already being treated with established therapies.

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Introduction

Inflammation accompanies the clinical syndrome of heart failure.1-6 The concentrations of

interleukin (IL)-1 and other inflammatory cytokines increase as heart failure worsens,2 and both

IL-6 and CRP concentrations predict death and correlate with exercise capacity in patients with

heart failure.3 Subsequent experimental studies demonstrated that expression of IL-1, tumor

necrosis factor (TNF)-, and other cytokines leads to changes in nitric oxide production, as well

as alterations in myocyte contractility and reversible left ventricular dysfunction and

remodeling.7-9 These observations spurred interest in anti-inflammatory therapies for prevention

or treatment of heart failure. Preclinical trials of etanercept and infliximab, two TNF inhibitors,

suggested improvements in left ventricular function and 6-minute walk distance.10, 11 However,

subsequent large, randomized trials of patients with established heart failure failed to reduce

heart failure, or increased the risk of death.12, 13

The intervening years have yielded improved understanding of inflammatory signaling in

myocardial biology and the development of left ventricular dysfunction.14 In particular,

experimental studies have demonstrated that myocardial response to injury and repair involves

activation of NFB and downstream activation of the NOD-like receptor pyrin-3 (NLRP3)

inflammasome and interleukin (IL)-1 and IL-18.15 A number of small randomized trials have

tested whether anakinra, an IL-1 receptor antagonist,16, 17 improves aerobic capacity. No

significant differences were observed between anakinra- and placebo-treated patients.17 No data

inform whether IL-1 inhibition can prevent clinical outcomes such as hospitalization for heart

failure or heart failure-related mortality. A prespecified exploratory analysis of the recently

reported CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) specifically

addressed whether IL-1 inhibition with canakinumab would improve heart failure outcomes. In

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addition, the enrollment criteria for CANTOS selected patients at increased risk for heart failure

by including those with both prior myocardial infarction and an elevated high-sensitivity C-

reactive protein (hsCRP).18

Methods

Study Design and Participants

CANTOS randomized 10,061 patients with prior myocardial infarction and hsCRP ≥ 2 mg/L to

canakinumab 50 mg, 150 mg, 300 mg, or placebo. Before randomization, participants were

asked if they had a history of heart failure (HF). This analysis included all patients regardless of

history of baseline history of HF, although we did repeat the analysis after stratifying by baseline

history of HF. The protocol was reviewed and approved by the responsible institutional review

board in all participating centers. The data, analytic methods, and study materials will not be

made available to other researchers for purposes of reproducing the results or replicating the

procedure.

Procedures

Patients enrolled in CANTOS had in-person visits with study staff at months 1.5, 3, and then

every three months thereafter. Patients were asked about any hospitalizations since the most

recent clinic visit, including hospitalization for heart failure (HHF). Canakinumab or placebo

was administered by subcutaneous injection at the time of each study visit. Baseline and 3-month

assessments of hsCRP and interleukin (IL)-6 were used to define baseline and on-treatment

hsCRP and IL-6 concentrations, respectively.

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Endpoint Ascertainment and Adjudication

Evaluating the effects of canakinumab on heart failure was a prespecified exploratory endpoint

of CANTOS. For this analysis, we focused on centrally validated HHF and HF-related

mortality. HHF was reported by the local CANTOS investigator via a structured event report

form. For patients admitted to the hospital with HF, investigators were asked to report patient

symptoms (dyspnea, decreasing exercise tolerance, orthopnea, paroxysmal nocturnal dyspnea, or

other symptoms), signs (rapid weight gain, rales on pulmonary exam, peripheral edema, weight

gain, or other signs), laboratory abnormalities (radiologic signs of heart failure, abnormalities in

B-type natriuretic peptide) and therapeutic intensification (intravenous [IV] diuretic therapy,

intensification of oral diuretic therapy, vasodilator therapy). On an a priori basis, the Clinical

Endpoints Committee Chair (Dr. B. M. Everett) adopted a consensus definition of hospitalization

for heart failure that required at least one symptom, two signs, and one therapeutic

intensification.19 Alternatively, a patient could have one symptom, one sign plus one laboratory

abnormality, and one therapeutic intensification.19 Reported cases of heart failure that did not

meet these criteria were not validated. In total, CANTOS collected 1018 reported HHF events in

602 individuals. Application of the above criteria validated 592 out of the 1018 reported HHF

events (58%). The 592 events occurred in a total of 385 unique patients enrolled in CANTOS. A

consort diagram for hospitalization for heart failure validation is presented in Supplemental

Figure 1. The time to the first HHF in each of those 385 unique patients comprised the primary

outcome of interest for this analysis.

For this analysis, we also assessed the effect of canakinumab on the composite endpoint

of the time to the first occurrence of a HHF or heart failure (HF)-related death. All deaths were

centrally adjudicated and classified as to cause, including heart failure/cardiogenic shock, by a

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Clinical Endpoints Committee of cardiologists blinded to study drug allocation. In addition, on

an a priori basis we also elected to present the effect of canakinumab on the composite outcome

of HHF plus cardiovascular (CV) death, HHF plus all-cause mortality, and the composite

outcome of HHF, non-fatal MI, non-fatal stroke, unstable angina requiring unplanned coronary

revascularization, or all-cause mortality.

Statistical Analysis

Baseline characteristics of the study population, stratified by the occurrence of HHF during

follow up, were compared using chi-square tests for categorical variables and Wilcoxon rank-

sum test for continuous variables.

Exploratory analyses sought to replicate previously published associations between

baseline concentrations of inflammatory biomarkers (hsCRP and IL-6) and the occurrence of

HHF during the trial follow up period.20 We divided baseline hsCRP and IL-6 concentrations

into increasing tertiles and calculated the risk of future HHF in Cox proportional hazards models

after adjusting for age, sex, race, and randomized treatment allocation (Model 1) and after the

further adjustment for diabetes, hypertension, body mass index, type of qualifying myocardial

infarction (MI), history of coronary artery bypass graft surgery, aspirin, baseline low-density

lipoprotein cholesterol (LDL-C), baseline estimated glomerular filtration rate (eGFR), and

baseline history of heart failure (Model 2). Of the 10,061 patients randomized in CANTOS,

10,054 and 5,058 had baseline concentrations of hsCRP and IL-6 available, respectively.

The time to the first HHF episode for the 385 unique patients with at least one episode of

HHF was the primary outcome variable. Our primary analysis included all patients regardless of

history of baseline history of HF, although we did repeat the analysis after stratifying by baseline

history of HF. We compared unadjusted incidence rates of HHF, HHF plus HF-related

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mortality, HHF plus cardiovascular mortality, HHF plus all-cause mortality, and the composite

of HHF, MI, stroke, unstable angina requiring unplanned coronary revascularization, or all-cause

mortality in the placebo and 50 mg, 150 mg, and 300 mg canakinumab groups. All incidence

rates are calculated based on person-time of observation and patients were censored at death, loss

to follow-up, or the end of the trial. Kaplan-Meier graphs and unadjusted log-rank p values

tested for differences between randomly allocated treatment groups. We used unadjusted Cox

proportional hazards to calculate the risk of HHF and the expanded composite endpoints among

those randomly allocated to each of the canakinumab doses versus placebo. We conducted two

sensitivity analyses to account for the competing risk of the CANTOS primary endpoint (a

composite of non-fatal MI, non-fatal stroke, or cardiovascular death), or the competing risk of

all-cause mortality. We tested the adequacy of the proportional hazards assumption in Cox

regression models using methods derived from the cumulative sums of martingale residuals over

follow-up times.21 To address the question of whether inflammation reduction related to effects

of canakinumab on HHF or to the composite outcomes noted above, we used the on-treatment

hsCRP concentration 3 months after randomization to define whether a patient had achieved the

pre-specified on-treatment threshold of interest (<2mg/L). In these analyses, we adjusted for

covariates known from prior analysis22, 23 to be related to on-treatment hsCRP concentrations,

including age, sex, race, diabetes, hypertension, body mass index (BMI), type of qualifying MI,

history of coronary artery bypass graft surgery, aspirin use, baseline hsCRP, baseline low-density

lipoprotein cholesterol, baseline estimated glomerular filtration rate, and baseline history of

chronic heart failure. All p-values are two sided.

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Results

CANTOS randomized 10,061 patients. Over a median follow up time of 3.7 years, we observed

at least one episode of HHF in 385 unique individuals. Patients with at least one episode of HHF

were older, had higher body mass index, and more likely had diabetes, hypertension, and prior

coronary bypass surgery (Table 1). Those who had HHF during follow up had higher median

(Q1, Q3) baseline concentrations of hsCRP and IL-6 than those who did not. Among patients

with HHF during the course of the trial, approximately 60% had a history of heart failure at

baseline. By contrast, among those who did not have an episode of HHF during the trial, 20%

had a history of heart failure at baseline.

Baseline concentrations of hsCRP and IL-6 associated with HHF (Supplemental Figures

2 and 3). This relationship persisted after adjustment for an array of potential confounders, with

individuals who had baseline hsCRP concentrations in the highest tertile at approximately 1.9

times the risk of HHF than those with hsCRP concentrations in the lowest tertile during the

course of the trial (hazard ratio (HR) 1.90, 95% CI 1.45-2.48; Supplemental Table 1). Those in

the highest as compared to the lowest tertile of IL-6 had similarly elevated risk (HR 2.16, 95%

CI 1.47-3.18; Supplemental Table 1).

The incidence rates per 100 person-years of a first episode of hospitalization for heart

failure were 1.12 in the placebo group, and in the canakinumab groups: 1.17 (50 mg), 0.96 (150

mg), and 0.85 (300 mg) (Table 2). The cumulative incidence of HHF, stratified by randomly

allocated treatment group, is displayed in Figure 1A. The unadjusted hazard ratios (95% CI) for

HHF with each dose of canakinumab compared to placebo were 1.04 (0.79-1.36) for 50 mg, 0.86

(0.65-1.13) for 150 mg, and 0.76 (0.57-1.01) for 300 mg (P-trend = 0.025) (Table 2). No

individual dose significantly reduced the rate of either the primary or secondary endpoint. In

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sensitivity analyses adjusted for the competing risk of the trial primary endpoint (a composite of

non-fatal MI, non-fatal stroke, or cardiovascular mortality; Supplemental Table 2), or the

competing risk of all-cause mortality, there were no substantial changes in our estimates of the

effect of canakinumab on HHF. The suggestion of a time-varying effect on HHF observed in

Figure 1 was supported by statistically significant evidence of a violation of the proportional

hazards assumption (P=0.03). When we analyzed HHF occurrence before the median event time

of 1.7 years separately from those that occurred after the median event time, we observed no

significant reduction in HHF risk for the early events, followed by a reduced risk of HHF with

randomly allocated 300 mg canakinumab for the later events (Supplemental Table 3).

We observed a similar dose-dependent reduction in the risk of the composite outcome of

HHF or HF-related mortality (Figure 1B). Specifically, the unadjusted hazard ratios (95% CI)

for HHF or HF-related mortality were 1.00 (0.78-1.30) for 50 mg, 0.87 (0.67-1.12) for 150 mg,

and 0.78 (0.60-1.01) for 300 mg (P-trend = 0.037; Table 2). Similar dose-dependent reductions

in the composite of HHF or cardiovascular death (Figure 2A), the composite of HHF or all-cause

mortality (data not shown), and the composite of HHF, non-fatal MI, non-fatal stroke, unstable

angina requiring unplanned coronary revascularization, or all-cause mortality (Figure 2B) were

seen with random allocation to canakinumab as compared to placebo (Table 2).

Among patients with a history of heart failure at trial entry, the incidence rates of HHF

events per 100 person years were 3.28 (placebo), 3.61 (50 mg canakinumab), 3.26 (150 mg

canakinumab), and 2.44 (300 mg canakinumab) (Table 3). Among patients without a history of

HHF at trial entry, the incidence rates of new HHF events per 100 person-years were 0.59

(placebo), 0.60 (50 mg), 0.43 (150 mg), and 0.42 (300 mg). We again observed a dose-

dependent reduction in the risk of HHF with increased doses of canakinumab that were similar in

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direction and magnitude for patients with and without a history of heart failure at baseline (Table

3).

Patients randomly allocated to canakinumab who achieved on-treatment hsCRP

concentrations <2 mg/L, regardless of dose, had significant reductions in HHF, HHF or HF-

related mortality, HHF or all-cause mortality, or HHF, MACE plus or all-cause mortality, while

those with on-treatment hsCRP concentrations ≥ 2 mg/L did not (Figure 3). For example, after

adjustment for potential confounders, including age, sex, race, diabetes, hypertension, body mass

index, type of qualifying MI, history of coronary artery bypass graft surgery, aspirin use,

baseline hsCRP, baseline LDL-C, baseline eGFR, and baseline history of chronic heart failure,

patients who achieved hsCRP < 2 mg/L had a 38% reduction in the relative risk of HHF

compared to placebo (HR 0.62, 95% CI 0.47-0.81), while those with on-treatment hsCRP

concentrations ≥ 2 mg/L did not (HR 1.03, 95% CI 0.81-1.31; Figure 3 and Supplemental Table

4). For those assigned to placebo who achieved an hsCRP < 2 mg/L, the risk of hospitalization

for heart failure was not significantly different from those in the placebo group who had an

achieved hsCRP ≥ 2 mg/L. Specifically, the hazard ratio (95% CI) of HHF was 0.93 (0.59-1.49).

Patients randomly allocated to canakinumab who achieved hsCRP concentrations < 2.0

mg/L had reductions in the composite outcomes of HHF or HF-related mortality, HHF or all-

cause mortality, and HHF or MACE plus or all-cause mortality (Figure 3 and Supplemental

Table 4). These effects among canakinumab-treated patients persisted when analyzed by

alternative on-treatment hsCRP thresholds, including achieved hsCRP concentrations above or

below the median achieved hsCRP of 1.8 mg/dL (Supplemental Table 5), or hsCRP reductions of

≥ 50% or <50% reduction (Supplemental Table 6), and by tertiles of achieved hsCRP

(Supplemental Table 7).

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Discussion

These randomized, double-blind, placebo-controlled data suggest that therapy with canakinumab,

an IL-1 inhibitor, is related to a dose-dependent reduction in hospitalization for heart failure

and the composite of hospitalization for heart failure or heart failure-related mortality in a

population of patients with prior MI and elevations in hsCRP. This study provides evidence that

baseline concentrations of the inflammatory biomarkers hsCRP and IL-6 independently associate

with future hospitalization for heart failure. While no single dose of canakinumab was

significantly different from placebo, inflammation inhibition with canakinumab was associated

with a significant dose-dependent trend in reduced rates of hospitalization for heart failure and

the composite of hospitalization for heart failure or heart failure-related mortality. The effect of

canakinumab on HHF applied to those with or without a prior history of heart failure.

Canakinumab consistently reduced composite endpoints that included HHF, such as HHF or all-

cause mortality or HHF, MACE plus, or all-cause mortality. Those in whom canakinumab

produced inflammation reduction evidenced by achieving on-treatment hsCRP concentrations <

2 mg/L showed substantial risk reductions in these composite endpoints.

These data have both scientific and clinical importance for a number of reasons. First,

considerable experimental and human biomarker data have long pointed to the involvement of

innate immunity in propagating key elements of myocardial dysfunction, and patients with

advanced heart failure have elevated markers of inflammation.1-3, 9, 14, 24, 25 The innate immune

system, including the NLRP3 inflammasome, contributes importantly to cardiac remodeling after

ischemic injury, leading to production of active IL-1 and to inflammatory cell accumulation in

the myocardium.15, 26 Experimental studies suggest IL-1 has deleterious but reversible effects

on myocardial energetics, beta adrenergic signaling, and contractility.7, 9, 24, 25, 27

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Age-dependent expansion of clones of hematopoietic cells that bear mutations that confer

a heightened risk of cardiovascular disease occur fairly commonly.28, 29 Mouse experiments have

shown that the most common mutation seen in that disorder (Tet2) may impair cardiac function

and remodeling in a mouse model of heart failure through enhanced IL-1 expression and

activation of the NLRP3 inflammasome.30 The present results suggest that among the pro-

inflammatory cytokines elevated in patients with heart failure, IL-1 plays a causal role rather

than merely serving as a biomarker of ongoing inflammation.

Our study differed from previously published randomized, controlled trials of infliximab

and etanercept both by specifically targeting IL-1, rather than TNF-, and because CANTOS

did not specifically enroll patients with established heart failure. As such, the rate of HHF in our

trial was lower than that observed in prior studies of TNF-. While pilot randomized trials of

etanercept, an inhibitor of TNF-, led to improvements in left ventricular function, quality of

life, and 6 minute walk distance,10, 11 a larger trial of infliximab suggested a higher risk of death

among those randomized to the higher dose of active therapy. Studies of etanercept halted early

for a lack of benefit for patients with established New York Heart Association Class II to IV

heart failure.12, 13

The exploratory data presented provide further support for targeting IL-1 to reduce the

morbidity and mortality associated with heart failure, a clinical syndrome of increasing

prevalence and importance. Current therapy for heart failure focuses on decongestion with

diuretics and modification of the neurohormonal pathways whose activation accompanies heart

failure but low blood pressure and azotemia often limit these therapies. Importantly, the data

presented here are from a population with high rates of renin-angiotensin-aldosterone system

antagonist use, and high rates of beta blocker use. IL-1 inhibition offers a mechanistically

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distinct and novel approach to therapy that leads to no clinically significant alterations in blood

pressure and does not aggravate renal dysfunction.31 The data presented here do not provide a

definitive test of the hypothesis that IL-1 inhibition improves outcomes in heart failure, but they

do suggest that targeting the NLRP3 inflammasome and IL-1 pathway in heart failure merits

pursuit in future clinical trials focused on a heart failure population.

Strengths and Limitations

CANTOS was a large, randomized, double-blind, placebo-controlled study, which minimizes the

chance that our observation results from confounding. The size and design of this study

reinforce the main observation of a significant dose-related trend towards a reduced rate of HHF

for patients randomly allocated to canakinumab in this analysis. We centrally validated all

episodes of HHF by applying a consistent, rigorous, specific definition of what constituted HHF

episodes. A number of limitations bear mentioning. While we know that all patients in

CANTOS had a history of MI, we do not know their ejection fraction or natriuretic peptide

concentrations at the time of randomization, or at the time of HHF. Thus, we are unable to

differentiate the effects of canakinumab on heart failure with reduced as compared to preserved

left ventricular function. We acknowledge that although no single dose of canakinumab as

compared to placebo demonstrated a statistically significant reduction in the risk of HHF, the

trend across all three doses was statistically significant. Although assessing the effect of

canakinumab on heart failure was a prespecified aim of CANTOS, the data presented here

should nonetheless be considered hypothesis generating. The achieved hsCRP on treatment

analyses are post-randomization, and thus subject to confounding. However, we adjust for

covariates that we know from analyses of the trial primary and secondary endpoints are related to

on-treatment hsCRP, but were unable to perform a causal inference analysis because of the

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number of HHF endpoints was too small. Nonetheless, we know from two prior studies with a

larger number of endpoints that the approach used here is valid.22, 23

Conclusions

In conclusion, these data suggest a therapeutic pathway of inflammation reduction that merits

further scientific and clinical exploration as a novel means to reduce hospitalization for heart

failure in selected patients. Readmissions for heart failure present an enormous human challenge,

and drain on health care resources that urgently demand new approaches. The present data, while

exploratory and hypothesis-generating, represent the first large-scale evidence indicating that IL-

1 targeted therapy may have a role in heart failure.

Sources of Funding

Funded by Novartis, Basel, Switzerland

Disclosures

PMR, and RJG received research grant support from Novartis Pharmaceuticals to conduct the

CANTOS trial. PMR, BME, PL, and AA have served as a consultants to Novartis. BME has

consulted for Roche Diagnostics and Amgen and has grant support from Novartis for work

unrelated to CANTOS. PMR is listed as a co-inventor on patents held by the Brigham and

Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease

and diabetes that have been licensed to AstraZeneca and Siemens. SDA received research grant

support for IITs from Vifor Int and Abbott Vascular. SDA received personal fees for

trial/registry related consultancy from Bayer, BioVentrix, Boehringer Ingelheim, Novartis,

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Servier, V-Wave. TT is an employee of, and holds stock in, Novartis Pharmaceuticals. All other

authors declare no competing interests.

References

1. Elster SK, Braunwald E and Wood HF. A study of C-reactive protein in the serum of

patients with congestive heart failure. Am Heart J. 1956;51:533-541.

2. Testa M, Yeh M, Lee P, Fanelli R, Loperfido F, Berman JW and LeJemtel TH.

Circulating levels of cytokines and their endogenous modulators in patients with mild to severe

congestive heart failure due to coronary artery disease or hypertension. J Am Coll Cardiol.

1996;28:964-971.

3. Deswal A, Petersen NJ, Feldman AM, Young JB, White BG and Mann DL. Cytokines

and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the

Vesnarinone trial (VEST). Circulation. 2001;103:2055-2059.

4. Vasan RS, Sullivan LM, Roubenoff R, Dinarello CA, Harris T, Benjamin EJ, Sawyer

DB, Levy D, Wilson PW, D'Agostino RB and Framingham Heart S. Inflammatory markers and

risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham

Heart Study. Circulation. 2003;107:1486-1491.

5. Kardys I, Knetsch AM, Bleumink GS, Deckers JW, Hofman A, Stricker BH and

Witteman JC. C-reactive protein and risk of heart failure. The Rotterdam Study. Am Heart J.

2006;152:514-520.

6. Kalogeropoulos A, Georgiopoulou V, Psaty BM, Rodondi N, Smith AL, Harrison DG,

Liu Y, Hoffmann U, Bauer DC, Newman AB, Kritchevsky SB, Harris TB, Butler J and Health

ABCSI. Inflammatory markers and incident heart failure risk in older adults: the Health ABC

(Health, Aging, and Body Composition) study. J Am Coll Cardiol. 2010;55:2129-2137.

7. Gulick T, Chung MK, Pieper SJ, Lange LG and Schreiner GF. Interleukin 1 and tumor

necrosis factor inhibit cardiac myocyte beta-adrenergic responsiveness. Proc Natl Acad Sci U S

A. 1989;86:6753-6757.

8. Bozkurt B, Kribbs SB, Clubb FJ, Jr., Michael LH, Didenko VV, Hornsby PJ, Seta Y,

Oral H, Spinale FG and Mann DL. Pathophysiologically relevant concentrations of tumor

necrosis factor-alpha promote progressive left ventricular dysfunction and remodeling in rats.

Circulation. 1998;97:1382-1391.

9. Tatsumi T, Matoba S, Kawahara A, Keira N, Shiraishi J, Akashi K, Kobara M, Tanaka T,

Katamura M, Nakagawa C, Ohta B, Shirayama T, Takeda K, Asayama J, Fliss H and Nakagawa

M. Cytokine-induced nitric oxide production inhibits mitochondrial energy production and

impairs contractile function in rat cardiac myocytes. J Am Coll Cardiol. 2000;35:1338-1346.

10. Deswal A, Bozkurt B, Seta Y, Parilti-Eiswirth S, Hayes FA, Blosch C and Mann DL.

Safety and efficacy of a soluble P75 tumor necrosis factor receptor (Enbrel, etanercept) in

patients with advanced heart failure. Circulation. 1999;99:3224-3226.

11. Bozkurt B, Torre-Amione G, Warren MS, Whitmore J, Soran OZ, Feldman AM and

Mann DL. Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in

patients with advanced heart failure. Circulation. 2001;103:1044-1047.

Dow


ovember 24, 2018


17

12. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT and Anti-TNF Therapy

Against Congestive Heart Failure Investigators. Randomized, double-blind, placebo-controlled,

pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in

patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against

Congestive Heart Failure (ATTACH) trial. Circulation. 2003;107:3133-3140.

13. Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, Colucci WS, Djian J, Drexler

H, Feldman A, Kober L, Krum H, Liu P, Nieminen M, Tavazzi L, van Veldhuisen DJ,

Waldenstrom A, Warren M, Westheim A, Zannad F and Fleming T. Targeted anticytokine

therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide

Evaluation (RENEWAL). Circulation. 2004;109:1594-1602.

14. Mann DL. Innate immunity and the failing heart: the cytokine hypothesis revisited. Circ

Res. 2015;116:1254-1268.

15. Mezzaroma E, Toldo S, Farkas D, Seropian IM, Van Tassell BW, Salloum FN, Kannan

HR, Menna AC, Voelkel NF and Abbate A. The inflammasome promotes adverse cardiac

remodeling following acute myocardial infarction in the mouse. Proc Natl Acad Sci U S A.

2011;108:19725-19730.

16. Van Tassell BW, Arena RA, Toldo S, Mezzaroma E, Azam T, Seropian IM, Shah K,

Canada J, Voelkel NF, Dinarello CA and Abbate A. Enhanced interleukin-1 activity contributes

to exercise intolerance in patients with systolic heart failure. PLoS ONE. 2012;7:e33438.

17. Van Tassell BW, Canada J, Carbone S, Trankle C, Buckley L, Oddi Erdle C, Abouzaki

NA, Dixon D, Kadariya D, Christopher S, Schatz A, Regan J, Viscusi M, Del Buono M,

Melchior R, Mankad P, Lu J, Sculthorpe R, Biondi-Zoccai G, Lesnefsky E, Arena R and Abbate

A. Interleukin-1 Blockade in Recently Decompensated Systolic Heart Failure: Results From

REDHART (Recently Decompensated Heart Failure Anakinra Response Trial). Circ Heart Fail.

2017;10:e004373. doi: 10.1161/CIRCHEARTFAILURE.118.005036.

18. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca

F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova

R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H,

Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ and Group CT. Antiinflammatory

Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377:1119-1131.

19. Zannad F, Garcia AA, Anker SD, Armstrong PW, Calvo G, Cleland JG, Cohn JN,

Dickstein K, Domanski MJ, Ekman I, Filippatos GS, Gheorghiade M, Hernandez AF, Jaarsma T,

Koglin J, Konstam M, Kupfer S, Maggioni AP, Mebazaa A, Metra M, Nowack C, Pieske B, Pina

IL, Pocock SJ, Ponikowski P, Rosano G, Ruilope LM, Ruschitzka F, Severin T, Solomon S,

Stein K, Stockbridge NL, Stough WG, Swedberg K, Tavazzi L, Voors AA, Wasserman SM,

Woehrle H, Zalewski A and McMurray JJ. Clinical outcome endpoints in heart failure trials: a

European Society of Cardiology Heart Failure Association consensus document. Eur J Heart

Fail. 2013;15:1082-1094.

20. Anand IS, Latini R, Florea VG, Kuskowski MA, Rector T, Masson S, Signorini S,

Mocarelli P, Hester A, Glazer R and Cohn JN; Val-HeFT Investigators. C-reactive protein in

heart failure: prognostic value and the effect of valsartan. Circulation. 2005;112:1428-1434.

21. Lin DY, Wei LJ and Ying Z. Checking the Cox model with cumulative sums of

martingale-based residuals. Biometrika. 1993;80:557-572.

22. Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ and Group CT.

Relationship of C-reactive protein reduction to cardiovascular event reduction following

Dow


ovember 24, 2018


18

treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled

trial. Lancet. 2017;391:319-328.

23. Ridker PM, Libby P, MacFadyen JG, Thuren T, Ballantyne C, Fonseca F, Koenig W,

Shimokawa H, Everett BM and Glynn RJ; CANTOS Trial Group. Modulation of the interleukin-

6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality:

analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS).

Eur Heart J. 2018;39:3499-3507.

24. Kacimi R, Long CS and Karliner JS. Chronic hypoxia modulates the interleukin-1beta-

stimulated inducible nitric oxide synthase pathway in cardiac myocytes. Circulation.

1997;96:1937-1943.

25. Van Tassell BW, Seropian IM, Toldo S, Mezzaroma E and Abbate A. Interleukin-1beta

induces a reversible cardiomyopathy in the mouse. Inflamm Res. 2013;62:637-640.

26. Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H, Izawa A,

Takahashi Y, Masumoto J, Koyama J, Hongo M, Noda T, Nakayama J, Sagara J, Taniguchi S

and Ikeda U. Inflammasome activation of cardiac fibroblasts is essential for myocardial

ischemia/reperfusion injury. Circulation. 2011;123:594-604.

27. Hosenpud JD, Campbell SM and Mendelson DJ. Interleukin-1-induced myocardial

depression in an isolated beating heart preparation. J Heart Transplant. 1989;8:460-464.

28. Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, McConkey M, Gupta

N, Gabriel S, Ardissino D, Baber U, Mehran R, Fuster V, Danesh J, Frossard P, Saleheen D,

Melander O, Sukhova GK, Neuberg D, Libby P, Kathiresan S and Ebert BL. Clonal

Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med.

2017;377:111-121.

29. Libby P and Ebert BL. CHIP (Clonal Hematopoiesis of Indeterminate Potential).

Circulation. 2018;138:666-668.

30. Sano S, Oshima K, Wang Y, MacLauchlan S, Katanasaka Y, Sano M, Zuriaga MA,

Yoshiyama M, Goukassian D, Cooper MA, Fuster JJ and Walsh K. Tet2-Mediated Clonal

Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1beta/NLRP3

Inflammasome. J Am Coll Cardiol. 2018;71:875-886.

31. Ridker PM, MacFadyen JG, Glynn RJ, Koenig W, Libby P, Everett BM, Lefkowitz M,

Thuren T and Cornel JH. Inhibition of Interleukin-1beta by Canakinumab and Cardiovascular

Outcomes in Patients With Chronic Kidney Disease. J Am Coll Cardiol. 2018;71:2405-2414.

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Table 1. Baseline characteristics of the CANTOS trial population, stratified according to

whether patients developed an episode of hospitalization for heart failure (HHF) during follow

up.

Characteristic

No Heart Failure

Hospitalization

(N=9676)

Heart Failure

Hospitalization

(N=385) P-value

Age 61 (54-68) 66(59-73) <.0001

Female Sex, N(%) 2493 (25.8%) 94 (24.4%) 0.55

White, N(%) 7715 (79.7%) 321 (83.4%) 0.08

Smoking, N(%) 0.11

Current 2286 (23.6%) 80 (20.8%)

Past 4551 (47.0%) 202( 52.5%)

Never 2839 (29.3%) 103 (26.8%)

Diabetes(%) 3797 (39.2%) 260 (67.5%) <.0001

Hypertension(%) 7647 (79.0%) 361 (93.8%) <.0001

Systolic blood pressure (mm Hg) 130 (120-140) 130(119-143) 0.69

Family History of myocardial infarction (%) 4090 (42.3%) 164 (42.6%) 0.90

Body mass index (kg/m2) 29.8 (26.5-33.7) 31.6 (27.9-36.9) <.0001

Qualifying myocardial infarction type 0.002

STEMI(%) 5302 (54.8%) 180 (46.8%)

NSTEMI(%) 3242 (33.5%) 142 (36.9%)

Unknown type or missing data 1132 (11.7%) 63 (16.4%)

History of PCI(%) 6460 (66.8%) 250 (64.9%) 0.45

History of CABG(%) 1295 (13.4%) 116 (30.1%) <.0001

Daily Exercise(%) 1658 (17.1%) 59 (15.9%) 0.34

Alcohol use(%,>1/day) 385(4.0%) 11 (2.9%) 0.27

Beta-blocker (%) 7972(82.6%) 339(88.2%) 0.004

Renin-angiotensin inhibitor(%) 7672(79.5%) 320(83.1%) 0.09

Diuretic(%) 3337(34.5%) 283(73.5%) <.0001

Mineralocorticoid receptor antagonist (%) 846(8.8%) 103(26.8%) <.0001

Aspirin(%) 8537 (88.4%) 300 (78.1%) <.0001

Other antiplatelet(%) 2716 (28.1%) 88 (22.9%) 0.03

Anticoagulant(%) 675 (7.0%) 86 (22.3%) <.0001

Statin(%) 8802 (91.0%) 355 (92.2%) 0.43

hsCRP(mg/L 4.2 (2.8-6.9) 5.7 (3.5-9.9) <.0001

Interleukin-6(ng/L) 2.6 (1.8-4.0) 3.9 (2.5-6.0) <.0001

Total cholesterol(mg/dL) 160.1 (136.1-189.1) 153.1 (133.0-186.4) 0.06

LDL cholesterol(mg/dL) 82.8 (63.8-107.1) 77.0 (60.0-104.0) 0.03

HDL cholesterol(mg/dL) 44.1 (37.0-52.2) 42.9 (35.0-52.0) 0.01

Triglycerides(mg/dL) 139.1 (101.9-194.9) 141.4 (98.3-205.0) 0.66

HbA1c (%) 5.9 (5.6-6.7) 6.6 (5.9 -8.0) <.0001

eGFR(mL/min/1.73m2) 79 (65-93) 70 (51-88) <.0001

History of chronic heart failure 1943 (20.1%) 230 (59.7%) <.0001

Abbreviations: CABG, coronary artery bypass graft surgery; eGFR, estimated glomerular filtration rate;

HbA1c, hemoglobin A1c; HDL, high-density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive

protein; LDL, low-density lipoprotein cholesterol; MI, myocardial infarction; NSTEMI, non-ST segment

elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST segment elevation

myocardial infarction

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Table 2. Rates of hospitalization for heart failure (HHF) among all randomized patients in CANTOS,

stratified by random allocation to placebo or one of three canakinumab doses.

Placebo

Canakinumab

50mg

Canakinumab

150mg

Canakinumab

300mg P-trend


N events/N at risk 139/3344 92/2170 82/2284 72/2263

Incidence Rate (95% CI) 1.12 (0.95-1.33) 1.17 (0.96-1.44) 0.96 (0.77-1.19) 0.85 (0.67-1.07)

Hazard ratio(95%CI) vs Placebo - 1.04(0.79-1.36) 0.86(0.65-1.13) 0.76(0.57-1.01) 0.025

P-value vs. Placebo - 0.79 0.28 0.06


or Heart Failure Mortality

N events/N at risk 158/3344 100/2170 95/2284 84/2263

Incidence Rate 1.28 (1.09-1.49) 1.28 (1.05-1.55) 1.11 (0.91-1.36) 0.99 (0.80-1.22)

Hazard ratio(95%CI) vs Placebo 1.00 (0.78-1.29) 0.88(0.68-1.13) 0.78(0.60-1.02) 0.042

P-value vs. Placebo 0.995 0.31 0.07


or Cardiovascular Mortality

N events/N at risk 327/3344 200/2170 201/2284 195/2263

Incidence Rate 2.64 (2.37-2.95) 2.55 (2.22-2.93) 2.35 (2.05-2.70) 2.29 (1.99-2.64)

Hazard ratio(95%CI) vs Placebo 0.94 (0.79-1.13) 0.90 (0.75-1.07) 0.87 (0.73-1.04) 0.11



or All-Cause Mortality

N events/N at risk 460/3344 284/2170 286/2284 273/2263

Incidence Rate 3.72 (3.39-4.07) 3.62 (3.23-4.07) 3.35 (2.98-3.76) 3.21 (2.85-3.61)

Hazard ratio(95%CI) vs Placebo 0.96(0.82-1.11) 0.90(0.78-1.05) 0.87(0.75-1.01) 0.045


Hospitalization for Heart

Failure, MI, stroke, unstable

angina requiring unplanned

coronary revascularization, or

all-cause mortality

N events/N at risk 780/3344 461/2170 460/2284 452/2263

Incidence Rate 6.75 (6.29-7.24) 6.19 (5.65-6.79) 5.67 (5.18-6.22) 5.59 (5.10-6.13)



Abbreviations: CI, confidence interval; MI, myocardial infarction

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Table 3. Rates of hospitalization for heart failure among patients with a baseline history of heart failure and

patients without a baseline history of heart failure.

Placebo

Canakinumab

50mg

Canakinumab

150mg

Canakinumab

300mg P-trend

History of Heart Failure at Baseline

N events/N at risk 80/721 54/451 52/478 44/523

Incidence Rate 3.28 (2.64-4.09) 3.61 (2.76-4.71) 3.26 (2.48-4.27) 2.44 (1.82-3.28)



No History of Heart Failure at Baseline

N events/N at risk 59/2623 38/1719 30/1806 28/1740

Incidence Rate 0.59 (0.46-0.77) 0.60 (0.44-0.82) 0.43 (0.30-0.62) 0.42 (0.29-0.60)



CI, confidence interval

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Figure Legends

Figure 1. The incidence of hospitalization for heart failure (Panel A), and hospitalization for

heart failure or heart failure related mortality (Panel B), among the CANTOS trial participants.

The groups are stratified by randomly allocated treatment group of placebo, canakinumab 50 mg,

150 mg, or 300 mg. The number at risk at each year is included in the table below each figure.

Figure 2. The incidence of hospitalization for heart failure or cardiovascular death (Panel A), or

the composite of hospitalization for heart failure, non-fatal myocardial infarction, non-fatal

stroke, unstable angina requiring unplanned coronary revascularization, or all-cause mortality

(Panel B). The groups are stratified by randomly allocated treatment group of placebo,

canakinumab 50 mg, 150 mg, or 300 mg. The number at risk at each year is included in the table

below each figure.

Figure 3. Adjusted hazard ratios for hospitalization for heart failure (HHF), HHF or heart

failure-related cardiovascular mortality (HHF or HF Death), HHF or cardiovascular mortality

(HHF or CV Death), HHF or all-cause mortality (HHF or All Death), and HHF, non-fatal

myocardial infarction, non-fatal stroke, unstable angina requiring unplanned coronary

revascularization, or all-cause mortality (HHF, MI, Stroke, Unstable Angina with Revasc, or All

Death). The hazard ratios (HRs) and 95% confidence intervals are after initiation of

canakinumab and stratified according to achieved concentrations of high-sensitivity C-reactive

protein (hsCRP) in the active therapy groups. The placebo group serves as the referent group for

the calculation of adjusted hazard ratios. The achieved hsCRP concentrations are ≥2 mg/L or < 2

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mg/L. Incidence rate (Inc Rate) and 95% confidence interval (CI) is per 100 person years of

observation, and patients are censored for death, lost to follow-up, or end of study. Estimates are

adjusted for age, sex, race, diabetes, hypertension, body mass index, type of qualifying

myocardial infarction, history of coronary artery bypass graft surgery, aspirin use, baseline

hsCRP, baseline low-density lipoprotein cholesterol, baseline estimated glomerular filtration

rate, and baseline history of chronic heart failure. Abbreviations: CI, confidence interval; CV,

cardiovascular; HF, heart failure; HHF, hospitalization for heart failure; HR, hazard ratio; MI,

myocardial infarction.

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0 1 2 3 4 5

0.00

0.02

0.04

0.06

0.08

0.10

Cum

ulat

ive

Inci

denc

e

PlaceboCanakinumab 50mgCanakinumab 150mgCanakinumab 300mg

Hospitalization for heart failure by randomized treatment assignment

Follow-up (years)No. at risk:Placebo 3344 3210 3103 2789 1369 243Canakinumab:

50mg 2170 2086 2013 1789 805 53150mg 2284 2190 2124 1916 961 229300mg 2263 2176 2103 1903 986 220

Figure 1A

P-trend=0.025

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0 1 2 3 4 5

0.00

0.02

0.04

0.06

0.08

0.10

Cum

ulat

ive

Inci

denc

e


Hospitalization for heart failure or heart failure related mortality by randomized treatment assignment


50mg 2170 2086 2013 1789 805 53150mg 2284 2190 2124 1916 961 229300mg 2263 2176 2103 1903 986 220

Figure 1B

P-trend=0.042

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0 1 2 3 4 5

0.00

0.05

0.10

0.15

0.20

0.25

0.30

Cum

ulat

ive

Inci

denc

e


Hospitalization for heart failure or cardiovascular mortality by randomized treatment assignment


50mg 2170 2086 2013 1789 805 53150mg 2284 2190 2124 1916 961 229300mg 2263 2176 2103 1903 986 220

Figure 2A

P-trend=0.11

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0 1 2 3 4 5

0.00

0.05

0.10

0.15

0.20

0.25

0.30

Cum

ulat

ive

Inci

denc

e


Hospitalization for heart failure or MACE-plus or all cause mortality by randomized treatment assignment


50mg 2170 2022 1901 1656 736 44150mg 2284 2116 2012 1793 875 196300mg 2263 2112 1990 1767 910 191

Figure 2B Hospitalization for heart failure, non-fatal myocardial infarction, non-fatal stroke, unstable angina requiring unplanned coronary revascularization or all-cause mortality by randomized treatment assignment

P-trend=0.001

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Figure 3

HHF HHF or HF Death HHF or CV Death HHF or All Death HHF, MACE+ or All Death

Achieved hsCRPPlacebo

>= 2< 2

Placebo

>= 2< 2

Placebo

>=2<2

Placebo

>= 2< 2

Placebo

>= 2< 2

N events135141

87

153155102

301290229

421416318

729636599

Inc Rate1.141.340.67

1.291.440.77

2.542.751.73

3.553.95

2.4

6.586.354.75

(95% CI)(0.96−1.35)(1.14−1.58)(0.53−0.80)

(1.10−1.51)(1.26−1.72)(0.63−0.93)

(2.27−2.84)(2.46−3.09)(1.52−1.96)

(3.23−3.90)(3.59−4.35)(2.15−2.68)

(6.12−7.08)(5.88−6.86)(4.39−5.15)

0.50 0.75 1.00 1.50 2.00

Adjusted HR (95% CI)

HHF, MI, Stroke, Unstable Angina with Revasc, or All Death

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