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Aims ST-segment elevation myocardial infarction (STEMI) is associated with an intense acute inflammatory response and an increased risk of death and heart failure (HF). In this study, we sought to evaluate the effect of anakinra, a recombinant interleukin-1 receptor antagonist, on the incidence of HF. Methods and results We performed a pooled analysis of three early phase randomized clinical trials. The endpoints included the composite of all-cause death and new-onset HF, and the composite of all-cause death and hospitalization for HF at 1-year follow-up. Safety events, including injection site reaction and serious infections, were also recorded. We analysed 139 patients with STEMI from three separate trials: VCUART (N = 10), VCUART2 (N = 30), and VCUART3 (N = 99). Of these, 84 (60%) patients were randomized to anakinra and 55 (40%) to placebo. Treatment with anakinra significantly reduced the incidence of all-cause death or new-onset HF (7 [8.2%] vs. 16 [29.1%], log-rank P = 0.002) and of all-cause death or HF hospitalization (0 [0] vs. 5 [9.1%], log-rank P = 0.007). Patients treated with anakinra had significantly higher injection site reactions (19 [22.6%] vs. 3 [5.5%], P = 0.016) without a significant difference in the incidence of serious infections (11 [13.1%] vs. 7 [12.7%], P = 0.435). Treatment with anakinra significantly reduced the area under the curve for high-sensitivity C-reactive protein between baseline and 14 days (75.48 [41.7–147.47] vs. 222.82 [117.22–399.28] mg day/L, P Conclusion IL-1 blockade with anakinra for 14 days in patients with STEMI reduces the incidence of new-onset HF or hospitalization for HF at 1 year following STEMI.

Background ST segment elevation myocardial infarction (STEMI) is associated with an intense acute inflammatory response and an increased risk of death and heart failure (HF). We analyzed the effect of recombinant interleukin-1 receptor antagonist (anakinra) 100 mg subcutaneous injection given once or twice daily for 14 days on the occurrence of HF in a pooled analysis of 3 clinical trials. Methods Enrollment criteria and study procedures were the same across the three studies. High-sensitivity C-reactive protein (CRP) was measured at baseline, 72 hours, and 14 days to construct an area under the curve (AUC0–14). Clinical events up to 1 year were adjudicated by an independent committee blinded to treatment allocation. Data for anakinra once daily and anakinra twice daily were pooled into a single anakinra group. CRP data are presented as median and interquartile range to allow for deviation from Gaussian distribution and non-parametric tests were used to evaluate differences between groups. Kaplan-Meier survival analyses were conducted and the intervention groups were compared using a log-rank test. Results Between 2008 and 2017, 139 patients with STEMI were enrolled. 84 patients were randomized to anakinra and 55 patients were randomized to placebo. Anakinra significantly reduced the CRP AUC0–14 (76 [42–147] vs 222 [117–339] mg*day/L; P Conclusions Treatment with anakinra for 14 days following STEMI blunts the inflammatory response and appears to reduce the occurrence of HF events at 1 year. These results support the hypothesis that early and targeted modification of the inflammatory response in STEMI may be a viable strategy to improve patient outcomes. Adjudicated events at 1 year Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Heart Lung and Blood Institute (USA), American Heart Association (USA)

Background ST-segment elevation myocardial infarction (STEMI) is associated with an intense acute inflammatory response further promoting cardiac dysfunction and heart failure (HF). Pilot proof-of-concept studies with anakinra, recombinant Interleukin-1 (IL-1) receptor antagonist, have shown feasibility and safety of IL-1 blockade in patients with STEMI. In the current study we analyzed the effects of anakinra on left ventricular (LV) dimensions and function in patients with STEMI. Methods We enrolled patients with STEMI within 12 hours of presentation at 3 sites in the United States of America. After revascularization, patients were randomly assigned to receive anakinra 100 mg twice daily, anakinra 100 mg once daily alternated with placebo once daily every 12 hours, or placebo twice daily, for 14 days in a 1:1:1 ratio. A transthoracic echocardiogram was completed within 24 hours of admission and at 1 year follow up to measure LV end-diastolic and end-systolic volumes (LVEDV and LVESV, respectively), stroke volume (SV) and ejection fraction (LVEF). (ClinicalTrials NCT01950299) Results Paired echocardiography studies (follow up study obtained 362 days [336–375] after the baseline study) were available in 63 of the 99 patients (63%): 23 of 35 patients in the placebo group (66%) and 40 of the 64 patients in the anakinra group (62%, P>0.05 for missing studies between the 2 groups; P>0.05 for duration of follow up). Baseline LVEDV, LVESV, SV and LVEF was not significantly different comparing placebo and anakinra (all P>0.05). Patients treated with anakinra had a significant improvement in LVEF from 49.8% (41.8–60.0%) to 54.0% (46.0–58.4%, P=0.028) and SV from 43.6 ml (37.6–52.1 ml) to 48.7 ml (40.9–62.5 ml, P=0.008), whereas no significant changes occurred within the placebo group (LVEF: from 51.7% [40.1–56.0%] to 53.5% [43.4–59.4%], P=0.25; SV: from 47.7 ml [40.1–56.8 ml], to 53.0 ml [44.9–57.4 ml], P=0.81). The between-groups differences, however, were not statistically significant. No significant changes were noted in LVEDV and LVESV in either group. The interval changes in CRP between admission and 72 hours, expression of the acute inflammatory response, inversely correlated with the LVEF at follow up (R=-0.30, P=0.026), with higher levels of CRP corresponding to lower LVEF values Conclusions A significant improvement in cardiac systolic function was seen in patients treated with IL-1 receptor antagonist, anakinra, following STEMI, and not in patients with placebo. Further studies are however required to determine whether the benefits of IL-1 blockade in the prevention and treatment of HF are mediated by the effects on cardiac function. Acknowledgement/Funding Funded by NHLBI 1R34HL121402; Drug supply from Swedish Orphan Biovitrum

Background ST-segment elevation myocardial infarction (STEMI) is associated with an intense acute inflammatory response and an increased risk of recurrent ischemic events. Prior studies of IL-1 blockade have shown conflicting results regarding the risk of future events. Methods We enrolled patients with STEMI within 12 hours of presentation at 3 sites in the United States of America. After revascularization, patients were randomly assigned to receive anakinra 100 mg twice daily, anakinra 100 mg once daily (standard dose) alternated with placebo once daily every 12 hours, or placebo every 12 hours for 14 days in 1:1:1 ratio. Prespecified exploratory endpoints for recurrent ischemic events, adjudicated by an independent committee, evaluated the composite risk of subsequent acute myocardial infarction (AMI, World Health Organization classification Type 1), unstable angina, or urgent revascularization. Data are expressed as median and interquartile range or number and percentage. Cox regression analysis was used to generate unadjusted hazard ratios and confidence intervals. (ClinicalTrials.gov number, NCT01950299) Results Of 311 patients screened, 99 subjects (81% males, 58% Caucasians, 55 [49–62] years of age) were randomly assigned to anakinra twice daily (N=31), anakinra once daily (N=33) or placebo (N=35). The cohort included patients with hypertension (57%), tobacco use (55%), diabetes mellitus (30%), and prior diagnosis of coronary artery disease (21%) without statistically significant imbalances in the demographic characteristics between groups (all P>0.05). Discharge medications for the index STEMI admission, in addition to the study medication, included aspirin (100%), statins (100%), P2Y12 inhibitors (100%), beta-blockers (90%), and angiotensin converting enzyme inhibitor/angiotensin receptor blocker (84%), without statistically significant imbalances between the 3 groups. Over the 1-year follow-up, recurrent ischemic events occurred in 5/35 (14.3%) patients treated with placebo and 6/64 (9.1%) patients treated with anakinra (hazard ratio = 0.68 [0.20–2.24], P=0.53). No differences were observed between high- and low-dose anakinra treatment groups. Conclusions A two week treatment with IL-1 receptor antagonist, anakinra, did not significantly decrease or increase recurrent ischemic events over the course of a 1-year follow-up in patients with STEMI. Acknowledgement/Funding Funded by NHLBI 1R34HL121402; Drug supply by Swedish Orphan Biovitrum

Background Takotsubo (stress) cardiomyopathy is an acute reversible heart failure syndrome initially described in Japanese patients, but now well characterized in Caucasians patients in Europe or of European descent. An initial observation has suggested a lower incidence of Takotsubo in non-Caucasian subjects, particularly in the African-American (AA) population in the United States of America. The purpose of this study was to assess whether epidemiologic and clinical differences were present in Takotsubo in a large urban hospital in Virginia, USA. Methods We used an informatics-based system to query electronic health records (TriNetX, Cambridge, MA, USA) to search for cases of Takotsubo between 2010 and 2018 and a corresponding cohort of patients with non-ST segment elevation acute myocardial infarction (NSTEMI). We then performed a chart-level review of 160 cases and obtained additional clinical information including symptoms, risk factors, co-morbidities, and in-hospital outcomes. This retrospective study was approved by the Institutional Review Board of our institution. Results We identified 260 cases of Takotsubo and 6,270 of NSTEMI in the same time period (1:24, 4.2%). Being AA was associated with an odds ratio of Takotsubo versus NSTEMI of 0.38 [0.29–0.50] (P=0.0001). With further evaluation of patients with Takotsubo (N=160), AA (N=44, 27.2%) and Non-Hispanic Caucasian (C) (N=110, 67.9%) had no differences in age and sex. AA patients with Takotsubo however were more likely than C patients to be affected by type II diabetes mellitus (38.6% versus 14.5%, P=0.002, OR 3.70 [1.65–8.28]), have history of drug abuse (27.3% versus 9.1%, P=0.009, OR 3.75 [1.48–9.49]) and of cocaine use in particular (9.1% versus 0.9%, P=0.024, OR 11.0 [1.19–101.4]). The pattern of wall motion abnormality was not different between the 2 groups. AA patients presented with a lower ratio of brain natriuretic peptide (BNP) to troponin I (41.9 [12.7–258] pg./ml versus 281 [42–890] pg/ml, P=0.022). There was no significant difference of in-hospital mortality between the AA and C groups (9.1% versus 25%, respectively, OR 0.40 [0.13–1.24], P=0.11). Conclusions The incidence and clinical characteristics of Takotsubo (stress) cardiomyopathy appear to be different between African-American and Non-Hispanic Caucasian patients. African-American patients are more likely to have diabetes and illicit drug usage, but have a lower BNP/troponin I ratio. Both AA and Non-Hispanic Caucasian patients have similar in-hospital mortality.

Background ST-segment elevation myocardial infarction (STEMI) is associated with an intense inflammatory response that predicts an increased risk of death and heart failure (HF). In the current study we tested whether anakinra, a recombinant Interleukin-1 (IL-1) receptor antagonist, given once daily (standard dose) or twice daily reduced systemic inflammation in patients with STEMI. Methods We enrolled patients with STEMI within 12 hours of presentation at 3 sites. After revascularization, patients were randomly assigned to receive anakinra 100 mg twice daily, anakinra 100 mg once daily alternating with placebo once daily every 12 hours, or placebo twice daily, for 14 days in a 1:1:1 ratio. The primary efficacy outcome was the area under the curve for C-reactive protein levels (CRP-AUC) using a high-sensitivity assay at 14 days comparing anakinra (both arms) versus placebo followed by a comparison between each of the anakinra arms with placebo. Two pre-specified exploratory clinical efficacy endpoints, adjudicated by a blinded event committee, were assessed: a composite endpoint of all-cause death for any reason or incidence of HF (defined as new-onset HF requiring hospitalization or a new prescription of a loop diuretic, D+HF) and a composite endpoint of death and HF hospitalization (D+HHF) at 1 year. Data are expressed as median and interquartile range or number and percentage. Kaplan-Meyer survival curves were compared using Log-rank test (Mantel-Cox). (ClinicalTrials.gov number, NCT01950299) Results Of 311 patients screened, 99 subjects (80 [81%] males, 57 [58%] Caucasians, 55 [49–62] years of age) were randomly assigned to anakinra twice daily (N=31), anakinra once daily (N=33) or placebo (N=35). There were no significant imbalances in the demographic characteristics between groups (all P>0.05). The CRP-AUC was significantly lower in the anakinra group than in the placebo group (67 [39–120] versus 214 [131–394] mg/dl, P Conclusions Among patients with STEMI, IL-1 blockade significantly reduced the systemic inflammatory response compared with placebo, without any significant difference between standard or high dose regimens. Prespecified exploratory analyses on clinical endpoints demonstrate reduced incidence of HF and reduced HF hospitalizations, supporting the concept of beneficial effects with IL-1 blockade in patients with acute myocardial infarction. Acknowledgement/Funding Funded by NHLBI 1R34HL121402; Drug supply from Swedish Orphan Biovitrum

Background ST-segment elevation myocardial infarction (STEMI) is associated with an intense acute inflammatory response and an increased risk of death and heart failure (HF). C-reactive protein (CRP) is the inflammatory biomarker most commonly used for risk stratification in patients with cardiovascular diseases. CRP levels are known to rise and fall during STEMI in response to myocardial injury. In this study, we analyzed whether admission CRP or delayed CRP (measured at 72 hours after admission) held a greater predictive value for adverse HF events in patients with STEMI. Methods We analyzed data from the VCUART3 clinical trial enrolling 99 patients with STEMI within 12 hours of presentation at 3 sites in the United States of America treated with anakinra or placebo. CRP levels were measured with a high-sensitivity assay at time of admission and again at 72 hours later. A dedicated committee composed of individuals not involved in the conduct of the trial adjudicated HF events including a composite endpoint of death from any reason or incidence of HF defined as new-onset HF requiring hospital admission or a new prescription for a loop diuretic (D+HF) and a composite endpoint of death and HF hospitalization (D+HHF) at 1 year. We used a time-dependent Cox-regression analysis to determine the association of CRP at admission or at 72 hours with the outcomes of interest in univariate and multivariate analysis. Data are presented as median and interquartile range. (ClinicalTrials NCT01950299) Results CRP levels from admission and 72 hours were available in 90 and 87 subjects respectively and they increased from 4.6 [2.8–8.5] mg/L to 11.6 [4.6–24.5] mg/L (P Conclusions Among contemporary patients with STEMI, the levels of CRP at 72 hours after admission was superior to admission CRP levels for predicting the incidence of HF events, and independent of NTproBNP levels. Our results indicate the importance of the inflammatory response during STEMI, supporting the concept of inhibiting the inflammatory response as a therapeutic strategy. Acknowledgement/Funding Funded by NHLBI 1R34HL121402; Drug supply from Swedish Orphan Biovitrum