Abstract
Cardiorespiratory fitness (CRF) in heart failure (HF) declines with age. Interleukin-1 (IL-1) is a pro-inflammatory cytokine involved in aging and HF. We aimed to determine the changes in CRF before and after treatment with anakinra, recombinant IL-1 receptor antagonist, in patients with HF stratified according to age below and above 60 years in phase II clinical trials. We analyzed data from 73 patients (37 [51%] female), 49 (67%) patients <60 years and 24 (33%) ≥60 years. All patients received anakinra 100 mg subcutaneously daily for a median of 4 (interquartile range from 2 to 12) weeks. We measured peak oxygen consumption (VO2peak) and high-sensitivity C-reactive protein (hsCRP). When compared with older patients, younger patients had higher baseline peak VO2 (15.2 [12.4–17.7] vs. 12.4 [10.3–14.3] mL·kg−1·min−1, p=0.001), yet no significant differences in hsCRP (6.6 [3.6-16.6] vs. 5.2 [2.7-11.2] mg/L, p=0.18). In both groups, anakinra decreased hsCRP (<60 years: −3.6 [−8.1 to −1.9] mg/L; p<0.001; ≥60 years: −2.7 [−9.0 to −1.4] mg/L; p<0.001) and increased peak VO2peak (<60 years: +0.5 [−0.9 – 2.5] mL·kg−1·min−1; p=0.036; ≥60 years: +1.1 [0.2 – 2.3] mL·kg−1·min−1; p<0.001). No significant differences in changes across time were observed between the age groups. Older patients with HF have a greater baseline impairment in CRF compared to younger patients despite similar levels of systemic inflammation, and they appear to have a similar improvement in CRF following treatment with anakinra. The lack of an active control group (placebo) is a significant limitation and additional studies are needed to validate and expand these findings assessing clinical outcomes.
Keywords: Heart Failure, C-reactive protein, Cardiopulmonary Exercise Test, Anakinra, Aging
Background
Heart failure (HF) remains a leading cause of morbidity and mortality globally, with rising prevalence attributed to the aging population and improved survival from cardiovascular diseases1. Systemic inflammation in HF is linked to worsened cardiac function and reduced cardiorespiratory fitness (CRF)2, which are critical determinants of quality of life3. Interleukin-1 (IL-1) is a pro-inflammatory cytokine which is central to the inflammatory burden seen in HF. IL-1 reduces cardiac systolic function and promotes adverse cardiac remodeling and HF after acute myocardial infarction4,5. In a phase III clinical trial of IL-1 blockade, canakinumab significantly reduce the incidence of HF-related events6, however, disappointing results were seen with other anti-inflammatory drugs like TNF blockers, colchicine, and myeloperoxidase inhibitors in patients with HF7. In phase II clinical trials, IL-1 blockade with recombinant human IL-1 receptor antagonist, anakinra, inhibited systemic inflammation and improved exercise capacity in patients with HF8–12. Further, aging itself is associated with chronic low-grade inflammation and dysregulated immune function13,14, as well as worsening of both CRF and quality of life3,15. IL-1 inhibition may especially benefit patients with clonal hematopoiesis driven by somatic mutations, in whom those of advanced age are at the greatest risk16. It is therefore important to determine whether younger and older patients with HF differentially benefit from IL-1 blockade. We aimed to determine the effect of anakinra on high sensitivity C reactive protein (hsCRP) levels and CRF variables in patients with HF stratified according to age below and above 60 years in phase II clinical trials of anakinra.
Methods
We pooled data from four previously published phase II clinical trials of HF patients treated with anakinra (Kineret®, Swedish Orphan Biovitrum, Waltham, MA, USA)8,10–12. Patients underwent blood sampling, transthoracic Doppler echocardiogram (TTE), and supervised maximal cardiopulmonary exercise testing (CPET) at baseline and during treatment. All original studies received approval from the Institutional Review Board and were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. All patients provided written informed consent.
CPET was conducted using a conservative ramping treadmill protocol. Measurements included peak oxygen consumption (peak VO2), minute ventilation to carbon dioxide production (VE/VCO2) slope, total exercise time, peak respiratory exchange ratio (RER), and oxygen uptake efficiency slope (OUES). For inclusion, peak RER must have reached ≥1.0. TTE assessments included left-ventricular ejection fraction (LVEF) and early mitral flow velocity to early mitral annulus tissue velocity (E/e′) ratio. Symptom burden and quality of life were evaluated using the Duke Activity Status Index (DASI) and Minnesota Living with Heart Failure (MLHFQ) questionnaire17,18. High-sensitivity CRP (hsCRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured at each visit, as surrogates of systemic inflammation and myocardial strain, respectively.
Individual patient data were pooled and analyzed. Continuous variables were reported as median [interquartile range], and categorical variables as numbers (percentages). Comparisons were made using Mann-Whitney U test for continuous variables and either chi-square or Fisher’s exact test for categorical variables. Within-group paired differences were compared using Wilcoxon signed-rank test. Multivariate linear regression was also used to determine whether age independently predicts the change in peak VO2, using baseline peak VO2 and comorbidities as predictors. A linear mixed-effects model was used to determine the effect of time (pre- vs post-treatment), age cohort, and an interaction on peak VO2. Fixed effects included atrial fibrillation, hypertension, hyperlipidemia, diabetes, and covariates included baseline peak VO2 and baseline NTproBNP level. A random-per-person intercept was applied to the model to adjust for person variability of the patients. Sensitivity analyses comparing both the peak VO2 in those > age 70, and the change in peak VO2 without the patients >age 70, was conducted using Wilcoxon and Mann-Whitney U tests as appropriate. A 2-sided p-value <0.05 was considered statistically significant. Analyses were performed using IBM SPSS Statistics (IBM, Armonk, NY, USA).
Results
Seventy-three patients who were treated with anakinra for 4 [2-12] weeks were included in the analysis and stratified according to age (n=49 <60 years, n=24 ≥60 years). There were no differences in New York Heart Association class or medications between groups (Table 1).
TABLE 1.
Clinical characteristics of the cohorts.
| Age < 60 years N=49 |
Age ≥ 60 years N=24 |
p-value | |
|---|---|---|---|
| Age (years) | 53 [44-55] | 67 [62-69] | <0.0001 |
| Female, n (%) | 23 (47%) | 14 (58%) | 0.36 |
| Black race, n (%) | 37 (76%) | 15 (63%) | 0.25 |
| BMI (kg/m2) | 37.2 [33.0 – 44.8] | 38.1 [29.7 – 42.8] | 0.87 |
| NYHA class II | 21 (43%) | 7 (29%) | 0.26 |
| NYHA class III | 28 (57%) | 17 (71%) | 0.26 |
|
| |||
| Medications | |||
| CAD, n (%) | 11 (22%) | 7 (29%) | 0.53 |
| DM, n (%) | 28 (57%) | 16 (67%) | 0.43 |
| HTN, n (%) | 42 (86%) | 24 (100%) | 0.05 |
| HLP, n (%) | 34 (69%) | 16 (67%) | 0.81 |
| ACE/ARB, n (%) | 37 (76%) | 21 (88%) | 0.23 |
| Beta-blocker, n (%) | 44 (90%) | 22 (92%) | 0.77 |
| MRA, n (%) | 25 (64%) | 8 (33%) | 0.15 |
|
| |||
| Adverse Events | |||
| Injection site reaction, n (%) | 8 (16%) | 4 (17%) | 0.99 |
| Infection, n (%) | 2 (4%) | 3 (12%) | 0.32 |
|
| |||
| Biomarkers | |||
| NT-proBNP baseline (pg/mL) | 323.5 [88.3 – 1462.8] | 627.5 [333 – 1786.3] | 0.11 |
| NT-proBNP on-treatment (pg/mL) | 261.5 [71.5 – 879.3] | 489.5 [302.5 – 1491.8] | 0.07 |
| Delta NT-proBNP (pg/mL) | −60.0 [−375.5 – 20.5] | −128.0 [−425.8 – 48.8] | 0.99 |
|
| |||
| CRP baseline (mg/L) | 6.6 [3.6 – 16.6] | 5.2 [2.7 – 11.2] | 0.18 |
| CRP on-treatment (mg/L) | 1.5 [0.9 – 3.8] | 1.0 [0.5 – 3.4] | 0.05 |
| Delta CRP (mg/L) | −3.6 [−8.1 – −1.9] | −2.7 [−9.0 – −1.4] | 0.49 |
|
| |||
| Cardiopulmonary Exercise Test | |||
| RER baseline | 1.08 [1.02 – 1.17] | 1.16 [1.07 – 1.27] | 0.03 |
| RER on-treatment | 1.13 [1.03 – 1.19] | 1.16 [1.05 – 1.22] | 0.24 |
| Delta RER | 0 [−0.04 – 0.09] | −0.01 [−0.07 – 0.09] | 0.37 |
|
| |||
| VO2peak baseline (mL·kg−1·min−1) | 15.2 [12.4 – 17.7] | 12.4 [10.3 – 14.3] | 0.001 |
| VO2peak on-treatment (mL·kg−1·min−1) | 16.0 [14.0 – 18.7] | 13.7 [11.7 – 15.8] | 0.007 |
| Delta VO2peak (mL·kg−1·min−1) | 0.5 [−0.9 – 2.5] | 1.1 [0.2 – 2.3] | 0.24 |
|
| |||
| VE/VCO2 slope baseline | 29.5 [26.2 – 34.9] | 32.8 [28.0 – 36.0] | 0.32 |
| VE/VCO2 slope on-treatment | 28.2 [24.9 – 32.4] | 30.9 [26.7 – 33.4] | 0.32 |
| Delta VE/VCO2 slope | −0.8 [−3.9 – 1] | −1.6 [−3.4 – 0.4] | 0.48 |
|
| |||
| Exercise time baseline (s) | 480 [325 – 600] | 377 [268 – 485] | 0.03 |
| Exercise time on-treatment (s) | 530 [400 – 650] | 432 [330 – 490] | 0.02 |
| Delta exercise time (s) | 50 [2 – 82] | 35 [4 – 114] | 0.72 |
|
| |||
| OUES baseline | 2.1 [1.8 – 2.5] | 1.6 [1.2 – 1.9] | <0.001 |
| OUES on-treatment | 2.1 [1.8 – 2.5] | 1.7 [1.4 – 2.3] | 0.003 |
| Delta OUES | 0.04 [−0.09 – 0.24] | 0.19 [−0.04 – 0.47] | 0.08 |
|
| |||
| Quality of Life | |||
| DASI baseline | 24.2 [16.2 – 36.7] | 24.2 [11.7 – 37.0] | 0.59 |
| DASI on-treatment | 32.2 [24.2 – 42.7] | 24.2 [17.7 – 39.7] | 0.19 |
| Delta DASI | 5.5 [0 – 13.5] | 0 [−0.9 – 7.4] | 0.09 |
|
| |||
| MLWHF baseline | 56 [38 - 68] | 45 [30 - 63] | 0.22 |
| MLWHF on-treatment | 42 [11 – 63] | 28 [15 – 57] | 0.64 |
| Delta MLWHF | −9 [−36 – 3] | −6 [−28 – 3] | 0.82 |
|
| |||
| Echocardiography | |||
| LVEF baseline (%) | 46 [33 – 60] | 41 [26 – 55] | 0.70 |
| LVEF on-treatment (%) | 45 [37 – 59] | 45 [29 – 57] | 0.54 |
| Delta LVEF (%) | −0.5 [−9.4 – 6.8] | 4.9 [−6.5 – 13.1] | 0.35 |
|
| |||
| E/e’ baseline | 12.9 [8.7 – 19.2] | 15.8 [13.9 – 23.3] | 0.03 |
| E/e’ on-treatment | 10.5 [8.1 – 14.0] | 14.7 [11.7 – 25.6] | 0.009 |
| Delta E/e’ | −2.2 [−7.0 – 0.4] | −1.2 [−3.8 – 2.3] | 0.32 |
BMI, body mass index; NYHA, New York Heart Association Classification; CAD, coronary artery disease; DM, diabetes mellitus; HTN, hypertension; HLP, hyperlipidemia; ACE, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blockade; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro-B-type natriuretic peptide; CRP, C-reactive protein; RER, respiratory exchange ratio; VO2, oxygen consumption; VE/VCO2, minute ventilation/carbon dioxide production; OUES, oxygen uptake efficiency slope; DASI, Duke activity status index; MLHFQ, Minnesota living with heart failure questionnaire; LVEF, left ventricular ejection fraction; E/e′, early mitral inflow velocity/early diastolic mitral annual velocity.
Baseline hsCRP was not statistically different between the two groups (<60 years: 6.6 [3.6 – 16.6] mg/L; ≥60 years: 5.2 [2.7 = 11.2] mg/L; p=0.18; Table 1). Anakinra significantly decreased hsCRP in both groups, with a similar change in both age groups (<60 years: −3.6 [−8.1 to −1.9] mg/L; ≥60 years: −2.7 [−9.0 to −1.4] mg/L; p=0.49; Figure 1A). NT-proBNP at baseline was also not different between the two groups, and with a similar change in NT-proBNP on anakinra across age groups (<60 years: −60.0 [−375.5 – +20.5] pg/ml; ≥60 years: −128.0 [−425.8 – +48.8] pg/ml; p=0.99).
Figure 1. Effects of anakinra on (A) high-sensitivity C-reactive protein levels (mg/L) and (B) peak VO2 (mL·kg−1·min−1) in heart failure patients, stratified by age group (<60 years and ≥60 years).
Both age groups show significant reductions in high-sensitivity C-reactive protein levels and improvements in peak VO2. Data are presented as medians with interquartile ranges.
Peak VO2 was significantly lower in patients ≥60 years at baseline (<60 years: 15.2 [12.4 – 17.7] mL·kg−1·min−1; ≥60 years: 12.4 [10.3 – 14.3] mL·kg−1·min−1; p=0.001; Figure 1B). Similarly, total exercise time and the OUES were significantly lower in patients ≥60 years at baseline. Despite these differences, anakinra significantly improved peak VO2 in both age groups (<60 years: +0.5 [−0.9 – 2.5] mL·kg−1·min−1; p=0.036; ≥60 years: +1.1 [0.2 – 2.3] mL·kg−1·min−1; p<0.001) with a similar change between groups p=0.24). Multivariate regression confirmed that age was not an independent predictor of the change in peak VO2 (B= −0.62, p=0.48). The linear mixed-effects model controlling for baseline covariates revealed that peak VO2 was significantly higher post-intervention compared with pre-intervention (F(1,52.2)=6.05, p=0.02). Baseline peak VO2 was a strong predictor of post-intervention values (F(1,45.1)=283.0, p<0.001). There was no significant effect of age group (p=0.71), and no time x age group interaction (p=0.56). Similarly, anakinra improved exercise time in both age groups (<60 years: +50 [2 – 82] seconds; p<0.001; ≥60 years: +35 [4 - 114] seconds; p=0.002) with a similar change between groups (p=0.72). Neither the change in OUES (<60 years: +0.04 [−0.09 – +0.24]; ≥60 years: +0.19 [−0.04 – 0.47]; p=0.08) nor VE/VCO2 slope (<60 years: −0.8 [−3.9 – +1.0]; ≥60 years: −1.6 [−3.4 – +0.4]; p=0.48) was significantly different between age groups (Table 1).
The LVEF was not significantly different between age groups at baseline (<60 years: 46 [33 – 60] %; ≥60 years: 41 [2 – 55] %; p=0.70), and the change on anakinra was not different between group (<60 years: −0.5 [−9.4 – 6.8]; ≥60 years: +4.9 [−6.5 – +13.1]; p=0.35). The E/e’ was significantly higher in patients ≥60 years at baseline (<60 years: 12.9 [8.7 – 19.2]; ≥60 years: 15.8 [13.9 – 23.3]; p = 0.03), however, the change in E/e’ on anakinra was not different between groups (<60 years: 2.2 [−7.0 – +0.4]; ≥60 years: −1.2 [−3.8 – 2.3]; p=0.32).
The DASI score was not different between age groups at baseline (<60 years: 24.2 [16.2–36.7]; ≥60 years: 24.2 [11.7–37.0]; p=0.59) or on-treatment (<60 years: 32.2 [24.2–42.7]; ≥60 years: 24.2 [17.7–39.7]; p=0.19), and the change in DASI score on treatment was not significantly different (<60 years: +5.5 [+0 - +13.5]; ≥60 years: +0 [−0.9 - +7.4]; p=0.09). The MLWHF score also showed no significant difference between age groups at baseline (<60 years: 56 [38–68]; ≥60 years: 45 [30–63]; p=0.22) or on treatment (<60 years: 42 [11–63]; ≥60 years: 28 [15–57], p=0.64). Similarly, the change in MLWHF score with treatment was not significantly different between groups (<60 years: −9 [−36 - +3]; ≥60 years: −6 [−28 - +3]; p=0.82; Table 1).
Sensitivity analyses were completed, showing no differences in outcomes when patients over age 70 were removed (all p>0.10). When examining only those age 70 or greater (n=5), peak VO2 increased +1.0 [+0.1 – +5.0] ml/kg/min; p=0.14.
The most common adverse events with anakinra were injection site reactions (<60 years: 8 [16%]; ≥60 years: 4 [17%]; p=0.99) and infection requiring antimicrobial medications (<60 years: 2 [4%]; ≥60 years: 3 [12%], p=0.32; Table 1).
Discussion
The results of this pooled analysis show a significant improvement in hsCRP levels and peak VO2 with anakinra in patients with heart failure without significant differences comparing those below or above age 60.
While aging is associated with systemic inflammation and worse cardiorespiratory fitness, this data support and expand prior data suggesting that IL-1 blockade may benefit patients with HF, and that these results may occur regardless of aging. The values of hsCRP were indeed similar in both patient cohorts prior to the treatment with anakinra, whereas peak VO2 was expectedly worse in the older cohort of patients. A similar improvement in hsCRP and peak VO2 was found between the two age cohorts after treatment with anakinra. The improvement in peak VO2 on anakinra in the pooled analysis was +6.7%, which has important implications as every 6% increase in peak VO2 is associated with an estimated 5% lower risk of mortality and hospitalization in patients with HF19. These data suggest that IL-1 mediated systemic inflammation inhibits peak VO2 in patients with HF regardless of age, and that reducing inflammation in these patients may indeed improve exercise capacity. The mechanisms by which the improvement occurs requires further research, but may be related to factors such as enhanced cardiac reserve as IL-1 reduces LV contractile function4. The rate of adverse events was also similar across both age cohorts, suggesting a similar safety profile of anakinra.
There are several limitations to this study. This sample size is a major limitation of this study, particularly the small number of patients over age 70 (n=5 [7%]). This may limit the external validity of the findings presented herein and might preclude any conclusions in an even older cohort of patients with HF. Further, sensitivity analyses conducted are underpowered and the results should be interpreted as such. Patients were treated across a range of treatment durations (4 [2-12] weeks) and it is possible that length of treatment may affect outcomes. Although the lack of placebo comparison is a significant limitation in this analysis, no significant changes in the parameters analyzed were shown to change with placebo in the original studies8,10,11. Regardless, it is possible that within-group changes seen here in a smaller cohort of patients could potentially be explained by placebo effect or regression to the mean.
In conclusion, patients with HF ≥60 years of age have worse CRF than those <60 years, as expected, despite similar degree of systemic inflammation as shown by hsCRP levels. Notwithstanding the limitations of the phase II clinical trials, this pooled analysis suggests that IL-1 blockade with anakinra may improve systemic inflammation and cardiorespiratory fitness in patients with HF similarly in both age cohorts, with no significant interaction between groups. While limited by lack of placebo-control, this suggests that the benefits of IL-1 blockade are independent of age-related changes in immune function. These data may be relevant for the design and conduct of additional studies required to validate and expand these findings, with larger sample sizes and larger recruitment of even older individuals who are not adequately represented in this analysis, and the assessment of clinical events.
FUNDING
This study is a pooled analysis of the D-HART trial supported by an American Heart Association Scientist Development grant (10SDG303005) to Dr. Abbate and by Clinical and Translational Science Award K12 training award (KL2RR031989) from the National Center for Research Resources to Dr. Van Tassell at Virginia Commonwealth University Center for Clinical and Translational Research; the DHART2 trial supported by a grant from the National Heart, Lung, and Blood Institute (1R34HL118348) to Drs Abbate and Van Tassell, a Clinical and Translational Science Award (UL1TR000058) from the National Center for Research Resources to the Virginia Commonwealth University Center for Clinical and Translational Research, and by Swedish Orphan Biovitrum (SOBI, Stockholm, Sweden) who provided the active drug (anakinra) and placebo free of charge; and the REDHART trial supported by a grant from the National Heart, Lung, and Blood Institute (1R34HL117026) to Drs Abbate and Van Tassell and by Swedish Orphan Biovitrum (SOBI, Stockholm, Sweden) who provided the active drug (anakinra) and placebo free of charge. No additional funding was provided for this analysis.
DISCLOSURES
Dr. Abbate has served as consultant to Kiniksa, Monte Rosa Therapeutics, and Novo Nordisk. Dr. Hogwood is supported by the NHLBI of the NIH under award T32HL007284. Dr. Canada is supported by the NHLBI of the NIH under award number K23HL159270. None of the other authors report any conflicts of interest regarding the content of this article.
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