Interleukin-1 Blockade in Patients With ST-Segment Elevation Myocardial Infarction with and without History of Coronary Artery Disease

Abstract

Background

Patients with a history of coronary artery disease (CAD) presenting with ST-elevation myocardial infarction (STEMI) have high risk. We aimed to determine whether patients with CAD history presenting with STEMI had greater systemic inflammation and/or whether they benefitted similarly from IL-1 blockade.

Methods.

We pooled data from three randomized clinical trials, including 139 patients with STEMI treated with anakinra or placebo. Patients were stratified by history of CAD defined as prior documented CAD, MI or coronary revascularization. The area under the curve (AUC) for C-reactive protein (CRP) was used to assess systemic inflammation. Event-free survival defined as the time from enrollment to the occurrence of a predefined adverse outcome, including new-onset heart failure, hospitalization for heart failure, or death, was compared using Cox regression analysis.

Results.

Of the 139 patients, 113 (81%) had no history of CAD, while 26 (19%) had a history of CAD. The CRP-AUC was significantly lower in the anakinra group compared placebo, independent of history of CAD: 85 [47-137] vs. 349 [154-580] mg·day/L for anakinra and placebo, respectively, in patients with history of CAD, and 86 [43-179] vs. 213 [115-341] mg·day/L in patients without CAD history; p for interaction= (0.27). No significant interactions were found between history of CAD and treatment allocation for the composite outcome for patients with and without history of CAD, respectively, p for interaction = (0.48).

Conclusion.

IL-1 blockade with anakinra in STEMI leads to similar reductions in systemic inflammation and improvement in HF-related outcomes inpatients both with and without history of CAD.

INTRODUCTION

Acute myocardial infarction is one of the leading causes of death in the developed world. The number of people dying from heart attacks in the United States each year has decreased from 1 in 2 to 1 in 8. However, heart disease remains the leading cause of death for men, women, and individuals across most racial and ethnic groups.^[1] During a myocardial infarction, a strong inflammatory response occurs in the heart, aiding in the healing of the infarct, but it may also contribute to maladaptive ventricular remodeling, leading to dilation and systolic dysfunction associated with morbidity and mortality.^[2]

Patients with a history of CAD who present with STEMI are at particularly high risk, often exhibiting a more advanced burden of atherosclerotic disease and a higher prevalence of microvascular dysfunction compared to those without a prior CAD history.^[3] These factors may predispose them to increased inflammation and myocardial injury. IL-1, a key pro-inflammatory cytokine, plays a central role in the acute inflammatory response during STEMI. ⁽²⁾ However, it remains unclear whether patients with a history of CAD who present with STEMI experience more pronounced systemic inflammation and whether they derive similar benefits from IL-1 blockade as those without a prior CAD history.

We hypothesize that patients with a history of CAD have a greater burden of cardiovascular risk factors and more extensive CAD, yet they derive similar benefits from IL-1 blockade with anakinra therapy after STEMI as those without a history of CAD, in terms of inflammation reduction and clinical outcomes. The aim of the present study was therefore to evaluate the impact of anakinra on systemic inflammation and HF-related events in a pooled analysis of patients with STEMI enrolled in three trials within the VCUART program comparing those with and without prior history of CAD.

METHODS

We performed a secondary analysis of three early phase randomized clinical trial in the Virginia Commonwealth University Anakinra Response Trial (VCUART) program.

Patients were enrolled at the Virginia Commonwealth University (Richmond, VA) for VCUART (from November 2008 to February 2009) and VCUART2 (September 2010 to May 2012) and at three clinical sites for VCUART3 (July 2014 to December 2017), including Virginia Commonwealth University, Virginia Cardiovascular Specialists (Richmond, VA), and Medstar Washington Hospital Center (Washington, DC).^[4,5,6].

Inclusion criteria

All three studies were structured with the same inclusion and exclusion criteria for patients with STEMI, presenting within 12 hours of chest pain onset and enrolled within 12 hours of reperfusion.

Exclusion criteria

Exclusion criteria included cardiac arrest, unsuccessful percutaneous coronary intervention, hemodynamic instability, prior STEMI, pre-existing congestive heart failure and/or severe left ventricular dysfunction (left ventricular ejection fraction [LVEF] <20%), severe aortic or mitral valve disease, pregnancy, chronic infections, autoinflammatory or autoimmune disease, or cancer. ^[4,5,6]

Patients in VCUART and VCUART2 were randomly assigned in a 1:1 ratio to anakinra 100 mg/day (Kineret; Swedish Orphan Biovitrum, Stockholm, Sweden) in 0.67 mL or matching NaCl (0.9%) placebo injected subcutaneously for 14 days.

Patients in VCUART3 were randomized 1:1:1 to anakinra 100 mg twice daily, anakinra 100 mg once daily plus placebo once daily, or placebo twice daily. The two anakinra arms of VCUART3 were pooled together for this analysis, as they individually reduced high-sensitivity C-reactive protein (hsCRP) versus placebo without significant differences between the two anakinra arms. ^[5]

Study procedures

We categorized the subjects into two groups, stratified by history of CAD defined as prior documentation of obstructive disease, prior MI or prior revascularization.

To evaluate the inflammatory response after STEMI, we compared the area-under-the-curve for hsCRP measured at baseline, 72 hours and 14 days using the linear trapezoidal method and expressed as mg·day/L.

The composite of all causes of death or new onset HF was defined using established criteria ^[4]. New onset HF was defined as dyspnea beginning or persisting >24 hours after admission with STEMI, associated with physical signs of heart failure and/or initiation or significant intensification of diuretics for the treatment of dyspnea (both criteria need to be met if event occurring during index hospitalization, one of the two is sufficient if the event occurs after discharge). Hospitalization for HF was defined as a hospitalization in which the primary reason was decompensated HF, established as the finding at admission of all 2 conditions: dyspnea or respiratory distress or tachypnea at rest or with minimal exertion; and evidence of elevated cardiac filling pressure or pulmonary congestion, defined by at least one of the conditions: pulmonary congestion/edema at physical exam OR chest X-Ray; plasma BNP levels ≥200 pg/mL; or invasive measurement of left ventricular end-diastolic pressure >18 mmHg or of pulmonary artery occluding pressure (wedge) >16 mmHg.

Clinical data were obtained from the case report forms at the in-person visit and from chart review. Events were censored at 12 months. Clinical events were adjudicated by independent cardiologists unaware of treatment allocation (VCUART and VCUART2) or adjudicated by an ad-hoc event-adjudicating committee, blinded to the identity of the individual and to treatment allocation as well as to the inflammatory biomarkers that may potentially be affected by treatment (VCUART 3).

Statistical analysis

Continuous variables are presented as mean ± SD or median [IQR], depending on data distribution – assessed with Shapiro-Wilk Test. Comparisons between groups were performed using Student’s T-test or the Mann-Whitney U test, as appropriate.

Categorical variables were presented as absolute numbers (percentage) and were compared using Chi-square or the Fisher’s exact test, as appropriate. Subgroup-by treatment interaction was evaluated fitting an ANCOVA model.

Event-free survival for both groups previous and no previous history of CAD was evaluated using Kaplan–Meier curves constructed for the time-dependent composite endpoint and compared via log-rank test. Proportional hazards assumption was confirmed through Schoenfeld residuals, and Cox-proportional hazards regression analysis was performed. Treatment effect homogeneity across the subgroups was assessed including an interaction term in the Cox-regression model.

The analyses were performed using SPSS, version 29.0 (IBM SPSS; Chicago, IL), R version 4.4.2 (R Foundation for Statistical Computing, Vienna, Austria) or Prism 10.0.2 (GraphPad Software Inc., San Diego, CA, USA).

RESULTS

The study population included 139 patients with STEMI from three randomized phase 2 clinical trials, 84 patients (60%) were randomized to anakinra and 55 (40%) to placebo. Of these, 113 patients (81.3%) had no history of CAD, while 26 patients (19%) had a history of CAD.

Of the 26 patients with a history of CAD, 21 (80%) had a history of percutaneous coronary intervention (PCI), 5 (19%) had undergone coronary artery bypass grafting (CABG), and 3 (11.5%) had experienced a prior non-ST-elevation myocardial infarction (NSTEMI). The clinical characteristics of the population are summarized in the Table 1. Patients with a history of CAD had a higher prevalence of comorbidities compared to those without CAD, including diabetes [n=10 (43%) vs n= 22 (25%); p = 0.07], hypertension [n= 15 (65%) vs n= 52 (60%); p = 0.77], hyperlipidemia [n=14 (60%) vs n=46 (53%); p = 0.75] and a prior stroke [n=15 (21%) vs n=9 (10%); p = 0.12; Table 1].

Table 1.

Demographic characteristics of patients with and without previous history of coronary artery disease (CAD).

	Without previous CAD (n= 113)	Previous CAD (n= 26)	p Value
Clinical characteristics
Age, years	55 [49-62]	56 [50-53]	0.84
Male sex at birth, n (%)	92 (82%)	18 (66%)	0.056
White/Caucasian, n (%)	69 (61%)	18 (66%)	0.74
Black/African American, n (%)	43 (38%)	9 (33%)	0.74
History of CAD
Prior PCI	n/a	21 (80%)	<0.001
Prior CABG	n/a	5 (19%)	<0.001
Prior NSTEMI	n/a	3 (11.5%)	<0.001
Diabetes mellitus, n (%)	22 (25%)	10 (43%)	0.07
Hypertension, n (%)	52 (60%)	15 (65%)	0.77
Tobacco use, n (%)	49 (57%)	11 (47%)	0.38
Hyperlipidemia, n (%)	46 (53%)	14 (60%)	0.75
Peripheral vascular disease, n (%)	6 (7%)	0	0.11
COPD, n (%)	4 (4.7%)	2 (8%)	0.64
Previous stroke, n (%)	9 (10%)	5 (21%)	0.12
Medication
Aspirin, n (%)	34 (30%)	5 (19%)	0.23
Statin, n (%)	35 (31%)	8 (31%)	0.94
β-Blocker use, n (%)	23 (20%)	7 (27%)	0.49
ACEi/ARB, n (%)	26 (23%)	7 (27%)	0.70
Laboratory data at baseline
WBC (x103/L)	11.5 [9-14]	10 [7.3-12]	0.085
Creatinine (mg/L)	1 [0.86-1.2]	0.8 [0.64-1.07]	0.19
eGFR, mL/min/1.73 m2	87 [68-101]	83 [66-97]	0.50
Hs-CRP (mg/L)	4.5 [2.2-8.7]	6.6 [3.4-11.3]	0.081
BNP (pg/mL)	46 [19-76]	76 [27-271]	0.17

Data are presented as median [interquartile range] and numbers (percentage). Abbreviations: COPD = Chronic obstructive pulmonary disease; ACEi/ARBs= angiotensin converting enzyme inhibitors/angiotensin receptor blockers; WBC = White blood cells; eGFR=estimated glomerular filtration rate; hsCRP = high-sensitivity C-reactive protein; BNP=B-type natriuretic peptide; PCI = Percutaneous coronary intervention; CABG = Coronary artery bypass grafting; NSTEMI= non-ST segment elevation myocardial infarction

Over a median follow-up of 365 (240-365) days, 22 patients (16%) developed new-onset HF, 15 were in the placebo group, seven in the anakinra group. (Table 2) Two patients (1%) both in the placebo cohort died, and five patients (4%) were hospitalized for decompensated HF.

Table 2.

Demographic characteristics of patients with and without history of CAD, allocated to anakinra or placebo.

	Without previous CAD (n=113)			Previous CAD (n= 26)
	Placebo (n= 47)	Anakinra (n= 66)	p-Value	Placebo (n= 8)	Anakinra (n= 18)	p-value
Clinical characteristics
Age, years	57 [51-65]	55 [47-60]	0.26	59 [51-64]	54 [49-61]	0.31
Male sex at birth, n (%)	42 (90%)	51 (77%)	0.09	6 (75%)	11 (61%)	0.49
White/Caucasian, n (%)	29 (61%)	41 (62%)	0.96	6 (75%)	11 (61%)	0.49
Black/African American, n (%)	18 (38%)	25 (37%)	0.96	2 (25%)	7 (39%)	0.49
History of CAD
Prior PCI	n/a	n/a	0	5(62%)	16(89%)	0.11
Prior CABG	n/a	n/a	0	2(25%)	3(16%)	0.61
Prior NSTEMI	n/a	n/a	0	2(25%)	1(5%)	0.15
Diabetes mellitus, n (%)	16 (34%)	12 (18%)	0.05	3 (37%)	8 (44%)	0.74
Hypertension, n (%)	33 (70%)	33 (50%)	0.032	4 (50%)	12 (66%)	0.42
Tobacco use, n (%)	26 (55%)	41 (62%)	0.46	3 (38%)	10 (57%)	0.39
Hyperlipidemia, n (%)	22 (46%)	35 (53%)	0.51	3 (37%)	11 (61%)	0.21
Peripheral vascular disease, n (%)	3 (6%)	7 (10%)	0.43	0 (0%)	0 (0%)	0
COPD, n (%)	5 (10%)	2 (3%)	0.098	0 (0%)	1 (5%)	0.49
Previous stroke, n (%)	6 (12%)	4 (6%)	0.21	4 (50%)	1 (6%)	0.008
Medication
Aspirin, n (%)	15 (31%)	19 (28%)	0.66	2 (25%)	3 (17%)	0.28
Statin, n (%)	15 (31%)	30 (30%)	0.78	3 (37%)	5 (28%)	0.80
β-Blocker, n (%)	8 (17%)	15 (22%)	0.73	1 (13%)	6 (33%)	0.37
ACEi/ARBs, n (%)	13 (27%)	13 (20%)	0.84	2 (25%)	5 (28%)	0.47
Laboratory data at baseline
WBC (x103/L)	11 [8-14]	12 [9-14]	0.26	14 [9-15]	8 [6-11]	0.019
Creatinine (mg/L)	1 [0.8-1.1]	1 [0.8-1.4]	0.74	1.1[0.76-1.6]	0.8 [0.6-1]	1
BNP (pg/mL)	35 [12-135]	24 [24-24]	0.60	52 [22-76]	119[38-278]	0.28
Hs CRP (mg/L)	4 [2-8]	4 [3-9]	0.25	7 [6-11]	6 [3-11]	0.56
eGFR, mL/min/1.73 m2	87 [68-100]	86 [67-103]	0.99	66 [40-103]	84 [75-97]	0.26

Data are presented as median [interquartile range] and numbers (percentage). Abbreviations: COPD = Chronic obstructive pulmonary disease; ACEi/ARBs= angiotensin converting enzyme inhibitors/angiotensin receptor blockers; WBC = White blood cells; eGFR=estimated glomerular filtration rate; hsCRP = high-sensitivity C-reactive protein; BNP=B-type natriuretic peptide; PCI = Percutaneous coronary intervention; CABG = Coronary artery bypass grafting; NSTEMI= non-ST segment elevation myocardial infarction.

Treatment with anakinra was associated with significantly lower hsCRP-AUC values compared with placebo, independent of history of CAD 85 [47-137] vs 349 [154-580] mg·day/L for anakinra and placebo, respectively, in patients with history of CAD, and 86 [43-179] vs. 213 [115-341] mg·day/L for anakinra and placebo, respectively, in patients without CAD history, for anakinra and placebo, respectively (p for interaction = 0.27; Table 3, Figure 1).

Table 3.

Differences in the area under the curve of high-sensitivity C-reactive protein (hsCRP-AUC) (mg·day/L) at 14 days within subgroups

Subgroup	Anakinra Median [IQR]	Placebo Median [IQR]	P-value	Interaction P-value
Prior history of CAD				0.27
Hx CAD	85 [47-137]	349 [154-580]	<0.001
No Hx CAD	86 [43-179]	213 [115-342	<0.001
Prior history of Statins				0.40
Statin	86 [47-120]	273 [163-546]	<0.001
No Statin	75 [43-192]	201[112-411]	<0.002
Prior history of Aspirin				0.54
Aspirin	75 [50-151]	267 [138-469]	<0.001
No Aspirin	90 [44-137]	213 [115-433]	<0.001

Data are presented as median [interquartile range]. Abbreviations: AUC = area-under-the-curve; Hx CAD = History of coronary artery disease; hsCRP = high-sensitivity C-reactive protein; IQR = interquartile range.

Figure 1.

Effect of the anakinra on area under the curve of high-sensitivity C-Reactive Protein (hsCRP-AUC) according to history of previous coronary artery disease (CAD).

In patients with a prior history of CAD, we observed three events out of 18 in the anakinra group and three events out of eight in the placebo group (HR 0.41 [0.08-2.07]). In the subgroup of patients without a prior history of CAD, four events out of 66 occurred in the anakinra group, compared to 13 events out of 47 in the placebo group (HR 0.21 [0.07-0.64]; Figure 2). No significant interaction was found between a history of CAD and treatment allocation to either anakinra or placebo for the composite outcomes (p for interaction = 0.48).

Figure 2. New-onset HF, HF hospitalization, or death in patients with STEMI stratified by Hx-CAD.

Kaplan–Meier curve showing event-free survival in patients with and without a prior history of coronary artery disease (CAD), comparing Anakinra vs Placebo.

As a sensitivity analysis, we repeated the assessments comparing those with treatment with aspirin or statins prior to admission for STEMI, as surrogates for history of CAD.

In the subgroup receiving aspirin prior to admission, patients treated with anakinra experienced three events out of 22, compared to six events out of 17 in the placebo group (HR 0.36 [0.09-1.47]). In the subgroup without aspirin treatment prior to admission, four events out of 61 were observed in the anakinra group, while 10 events out of 37 occurred in the placebo group (HR 0.15 [0.07-0.76] (Figure 3)

Figure 3. New-onset HF, HF hospitalization, or death in patients with STEMI stratified by Aspirin use;

Kaplan–Meier curve showing event-free survival among patients with or without prior aspirin treatment, comparing Anakinra vs Placebo.

In the cohort receiving statins prior to admission, we observed four events out of 25 in the anakinra group and 5 events out of 18 in the placebo group (HR 0.57 [0.15-2.15]). In contrast, in the cohort without statins prior to admission, there were three events out of 58 in the anakinra group and 11 events out of 36 in the placebo group (HR 0.15 [0.04-0.56]) (Figure 4).

Figure 4. New-onset HF, HF hospitalization, or death in patients with STEMI stratified by Statin use.

Kaplan–Meier curve showing event-free survival among patients with or without prior statin treatment, comparing Anakinra vs. Placebo

We found no significant interaction between aspirin or statin use prior to admission with effects of anakinra on HF-related outcomes (p for interaction = 0.61 and 0.14, for aspirin and statins use, respectively).

Similarly, we evaluated hsCRP-AUC levels in subgroups based on aspirin use. No significant interaction was found between hsCRP-AUC levels and treatment allocation (p for interaction = 0.54). In patients treated with aspirin, values were 75 [50–151] for anakinra vs 267 [138–469] mg·day/L for placebo (p < 0.001). Among those not receiving aspirin, hsCRP-AUC values were 90 [44–137] vs. 213 [115–433] mg·day/L, for anakinra and placebo groups respectively, respectively (p < 0.001; Table 3, Figure 5).

Figure 5.

Effect of the anakinra on area under the curve of high-sensitivity C-Reactive Protein (hsCRP-AUC) according to previous treatment with aspirin.

Additionally, we analyzed hsCRP-AUC levels in subgroups of patients with STEMI who were treated with or without statins and received either anakinra or placebo. No significant interaction was observed between hsCRP-AUC levels and treatment allocation (p for interaction=0.40). Among patients on statins, hsCRP-AUC values were 86 [47–120] for anakinra vs 273 [163–540] mg·day/L for placebo (p < 0.001). In patients not receiving statins, the values were 75 [43–192] vs 201 [112–411] mg·day/L, for anakinra and placebo groups respectively (p = 0.002; Table 3, Figure 6).

Figure 6.

Effect of the anakinra on area under the curve of high-sensitivity C-Reactive Protein (hsCRP-AUC) according to previous treatment with statins.

Forrest plot analysis is shown (Figure 7).

Figure 7.

Forest plot showing hazard ratio (HR) and 95% confidence interval (CI) for heart-failure free survival comparing anakinra vs. placebo, overall and stratified by prior history of coronary artery disease (CAD), prior use of aspirin (ASA), and prior use of statins. No significant interaction was observed between treatment effect and prior use of CAD, ASA, or statins.

DISCUSSION

The present analysis suggests that the benefits of IL-1 blockade with anakinra in patients with STEMI do not appear to differ according to prior history of CAD or previous treatment with statins or aspirin.

The presence of comorbidities and prior CAD are significant risk factors for adverse events and mortality in patients with acute coronary syndrome.^[8] Previous studies have reported that patients with prior CABG tend to have significantly higher mortality at both 30 and 180 days compared to those bypass surgery naïve.^[9] Similarly, patients who have undergone PCI are often characterized by more diffuse involvement of multiple coronary vessels and impaired left ventricular function, both of which contribute to worse prognosis.^[10] Our findings align with these observations, further underscoring the role of prior CAD as being associated with more comorbid conditions and a determinant of both short- and long-term outcomes in STEMI patients.

The objective of this study was to assess whether stratifying patients by pre-existing CAD would identify a subgroup deriving differential benefit from anakinra; however, no such interaction was observed. While evidence from phase II trials may inform the optimal design of phase III studies, these findings do not support the use of prior CAD as an enrichment criterion; Ongoing phase III trials will be necessary to determine who truly benefits from IL-1 blockade. This observation may be of particular relevance given that ongoing phase III trials employ enrichment strategies for enrollment, including prior CAD.

Along the same line, several studies have highlighted the prognostic value of pre-existing treatment such as aspirin, beta-blockers, and statins has been associated with improved survival following STEMI. ^[11,12] Interestingly, in our cohort, we observed a relatively low prevalence of prior aspirin use among patients with CAD compared to those without a prior history of CAD. In contrast, the use of beta-blockers, ACE inhibitors, and statins was more prevalent in patients with CAD, reflecting partial adherence to secondary prevention therapy. It is important to note that the classification of prior CAD was based on clinical history documented at the time of admission, which may be subject to limitations. Consequently, some patients with undocumented CAD could have been prescribed atherosclerosis-related medications such as aspirin or statins, which motivated the sensitivity analysis.

Importantly, IL-1 blockade has been previously associated with reduced systemic inflammation and improved cardiovascular outcomes in STEMI patients, with consistent efficacy across varying degrees of CAD complexity^[13], as well as across gender ^[14], and ethnic backgrounds ^[15]. However, the specific interaction between pre-existing CAD and the response to anti-inflammatory therapies remains insufficiently explored.

While a reduction in hsCRP levels does not necessarily guarantee a proportional reduction in cardiovascular risk, post-hoc analyses of the CANTOS trial ^[16] have shown that patients achieving hsCRP levels <2 mg/L experienced significant reductions in both cardiovascular and all-cause mortality. In line with these findings, our study also demonstrated a reduction in hsCRP levels alongside improvement in primary clinical outcomes, reinforcing the potential of anti-inflammatory therapies in improving prognosis particularly in patients with a history of CAD who may otherwise remain at elevated residual inflammatory risk despite conventional treatment.

Furthermore, our results align with those of the PROSPECT II study, which found that non-culprit lesions with high lipid content were associated with an increased risk of adverse cardiovascular events. These findings underscore the importance of assessing plaque characteristics and suggest that underlying inflammatory burden may significantly influence clinical outcomes.^[17]

Finally, our results highlight the need for a comprehensive and individualized approach to the management of STEMI patients, especially those with prior CAD and associated comorbidities. Anti-inflammatory strategies such as IL-1 blockade may provide additional benefit beyond current standard therapies, warranting further investigation in larger, dedicated trials.

Limitation of the Study

This study has several limitations; The relatively small sample size may have reduced the statistical power to detect meaningful differences between groups.

Additionally, the uneven distribution of participants, particularly within the subgroup with prior CAD, could have introduced selection bias.

Moreover, as a secondary analysis of a pooled cohort from phase II studies, the findings are constrained by the small numbers. Nevertheless, insights from these trials can inform the design of future phase III studies, and the current data do not support the use of prior CAD as an enrichment criterion.

CONCLUSION

No significant differences were observed in the inflammatory response between patients with and without a history of CAD following STEMI. IL-1 blockade with anakinra in STEMI results in reduced systemic inflammation and improved HF-related outcomes, regardless of the presence or absence of a prior CAD history.

Abbreviation and Acronyms

AUC-CRP

The area under the curve for C-reactive protein

CAD

coronary artery disease

HF

Heart Failure

IL-1

Interleukin-1

LVEF

left ventricular ejection fraction

STEMI

ST-elevation myocardial infarction

VCUART

Virginia Commonwealth University Anakinra Response Trial