Abstract
Patients with ST elevation myocardial infarction (STEMI) are at risk of future heart failure (HF), particularly those with anterior STEMI. Interleukin-1 (IL-1) is a key mediator of the inflammatory response, and its blockade has emerged as a potential therapeutic strategy to prevent HF events. The aim of this analysis was to explore the effects of anakinra, an IL-1 receptor antagonist, on HF outcomes based on anterior versus non-anterior location STEMI and to explore whether this effect is mediated through the amelioration of left ventricular systolic function and cardiac remodeling. We pooled data from three early phase randomized clinical trials. The primary endpoint was a composite of all-cause death and new-onset HF at 1 year follow-up. The left anterior descending coronary artery as culprit vessel was used to identify anterior STEMI. We included 139 patients, 47 (34%) with anterior STEMI and 92 (66%) with non-anterior STEMI. Anakinra significantly reduced the combined endpoint of death or new onset HF in patients with anterior STEMI (4 (13%) vs 7 (42%), log-rank p value=0.049) as well as in patients with non-anterior STEMI (3 [6%] vs 9 [24%], log-rank p value= 0.014). We found no significant differences comparing anakinra versus placebo in interval changes in left ventricular ejection fraction (LVEF) and volumes in anterior and non anterior STEMI. In conclusion, anakinra is associated with a reduction of heart failure events in patients with STEMI, irrespective of anterior or non-anterior location, or of changes in LVEF or cardiac remodeling.
Keywords: anakinra, IL-1, IL-blockade, acute myocardial infarction, STEMI, heart failure, anterior, left anterior descending coronary artery
Introduction
Early revascularization and pharmacological therapies have revolutionized the treatment and prognosis of ST elevation acute myocardial infarction (STEMI) (1). However, STEMI is still associated with a significant risk of heart failure (HF) events at follow-up (2–5). The excessive inflammatory response occurring after acute myocardial infarction (AMI) contributes to myocardial injury, adverse ventricular remodeling, systolic and diastolic dysfunction and eventually HF (6–8). Anterior STEMI due to the acute occlusion of the left anterior descending (LAD) coronary artery generally compromises a higher amount of myocardium, leading to worse in-hospital clinical course and adverse cardiovascular outcomes over time (9–11).
Interleukin-1 (IL-1) is a key mediator of the inflammatory response, and its blockade has emerged as a potential therapeutic strategy to prevent HF events following AMI (12). Recently, canakinumab, an IL-1β blocker, has shown to prevent the recurrence of atherothrombotic events and HF hospitalization in the stable setting of patients with a prior AMI (13,14). In three small, randomized control trials, Anakinra, an IL-1 receptor antagonist, administered during the acute phase of STEMI was associated with a reduction of the composite endpoint of all-cause death or new onset HF at 1 year of follow-up compared to placebo (15–18). The aim of this analysis was to explore the effects of anakinra on HF outcomes according to whether patients had an anterior or non-anterior location STEMI and to explore whether this effect is mediated through the amelioration of left ventricular systolic function and cardiac remodeling.
Methods
We performed a secondary analysis of the data from three Virginia Commonwealth University Anakinra Response Trial (VCUART) clinical trials (15,16,18). The VCUART program includes three randomized clinical trials registered in www.clinicaltrials.gov (NCT00789724, NCT00175018, and NCT01950299) and published separately (15,16,18). The patient level pooled data analysis was recently published (19). All three trials have similar inclusion and exclusion criteria, including adult patients with STEMI presenting within 12 hours of pain onset, enrolled within 12 hours of reperfusion and randomized to anakinra 100 mg/day (Kineret; Swedish Orphan Biovitrum, Stockholm, Sweden) or matching placebo for 14 days. The VCU-ART3 included an additional arm randomized to anakinra 100 mg twice daily; for the purposes of this pooled analysis, all patients randomized to anakinra were analyzed together (15,16,18). The exclusion criteria included cardiac arrest, unsuccessful percutaneous coronary intervention, hemodynamic instability, pre-existing severe congestive HF 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.
For the purpose of this analysis, anterior and non-anterior STEMI were defined according to the involvement of the LAD artery as the culprit vessel for anterior STEMI, and non-LAD artery for non-anterior STEMI.
The composite of all-cause death and new-onset HF was meaured using criteria established by a consensus document on the definition of HF after MI (19). Clinical data were obtained from the case report forms at the in-person visits and from chart review. Events were censored at 12 months. Clinical events were adjudicated by two independent cardiologists unaware of treatment allocation (VCUART and VCUART2) or by a blinded independent committee (VCUART3).
Subjects underwent a transthoracic Doppler echocardiogram within 24 hours of enrollment and at follow-up, after 3 months in VCUART (15) and VCUART2 (16) and 12 months in VCUART3 (18). Measurements of LV end-diastolic and end-systolic volumes (LVEDV and LVESV) and calculation of LV ejection fraction occurred off-line at the end of the study by a core laboratory with 2 separate operators blinded to group allocations. The average of the 2 measurements was used for measures differing ≤10%, whereas those with >10% difference were rereviewed by a third operator and discussed to achieve consensus, as previously described (15,16,18).
Continuous variables are reported as median and interquartile range (IQR); comparison between four groups was performed using Kruskal-Wallis Test with Mann–Whitney U test to compare between anterior and non-anterior or between anakinra and placebo. Categorical data are reported as number and percentage and were compared using the Chi Square test or Fisher’s exact test as appropriate. Kaplan-Meier curves for event-free survival were constructed for the time-dependent composite endpoints and compared using the log-rank (Mantel-Cox) test. The analyses were completed using SPSS, version 24.0 (SPSS; Chicago, IL).
Results
A total of 139 patients were enrolled between the three studies. A total of 84 (60%) patients were randomized to anakinra and 55 (40%) to placebo. The median duration of patient follow-up was 365 [240–365] days. Forty seven (34%) of the patients had anterior STEMI, and 92 (66%) had non-anterior STEMI. All patients with culprit LAD had ST elevation in the anterior (V2-4) or anteroseptal (V1-3) leads whereas none of the patients classified as non-anterior STEMI had ST elevation in the anterior or anteroseptal leads. None of the patients with left internal mammary artery bypass graft or patients with rare anatomical variants.
Compared to those with non-anterior STEMI, patients with anterior STEMI had a shorter symptom to balloon time (140 min [80–314] vs 180 min [125–387], p=0.041) (Table 1). Patients with anterior STEMI had a trend toward greater peak creatine kinase myocardial band (CK-MB) levels as compared with those with non-anterior STEMI (187 [42–287] ng/mL vs 108 [49–222] ng/mL, p=0.070) (Table 1).
Table 1.
Characteristics of the patients according to the anterior or non-anterior STEMI location.
| Anterior STEMI (N=47) | Non-anterior STEMI (N=92) | P value | |
|---|---|---|---|
| Clinical Characteristics | |||
| Age (median, IQR) | 54 [49–61] | 56 [50–64] | 0.545 |
| Male (%) | 36 (77%) | 74 (80%) | 0.598 |
| White (%) | 27 (57%) | 60 (65%) | 0.370 |
| Black (%) | 20 (43%) | 32 (35%) | 0.370 |
| BMI (median, IQR) | 30 [26–34] | 30 [26–35] | 0.824 |
| Diabetes mellitus (%) | 14 (30%) | 25 (27%) | 0.746 |
| Hypertension (%) | 28 (60%) | 54 (59%) | 0.921 |
| Tobacco use (%) | 31 (66%) | 49 (53%) | 0.204 |
| Dyslipidemia (%) | 22 (47%) | 49 (53%) | 0.472 |
| Previous history of CABG (%) | 1 (2%) | 5 (5%) | 0.664 |
| Chronic obstructive pulmonary disease (%) | 3 (6%) | 5 5%) | 0.820 |
| Medication at admission | |||
| Beta-Blocker (%) | 10 (21%) | 20 (22%) | 0.949 |
| Aspirin (%) | 11 (23%) | 28 (30%) | 0.382 |
| ACEi/ARB (%) | 9 (19%) | 26 (28%) | 0.241 |
| Statin (%) | 13 (28%) | 30 (3%) | 0.550 |
| Metformin (%) | 6 (13%) | 13 (14%) | 0.824 |
| Colchicine (%) | 0 (0%) | 0 (0%) | - |
| Clinical presentation | |||
| Thrombolysis (%) | 4 (9%) | 10 (11%) | 0.662 |
| Symptoms to balloon time (min) | 140 [80–314] | 180 [125–387] | 0.041 |
| Angiographic data | |||
| Culprit vessel (%) | - | ||
| Left anterior descending | 47 (100%) | 0 (0%) | |
| Circunflex | 0 (0%) | 26 (28%) | |
| Right coronary artery | 0 (0%) | 64 (70%) | |
| Safein vein graft | 0 (0%) | 2 (2) | |
| TIMI flow 0/1 pre-PCI (%) | 42 (89%) | 75 (82%) | 0.230 |
| TIMI flow 3 post-PCI (%) | 45 (96%) | 88 (96%) | 1 |
| Coronary artery stenting (%) | 44 (94%) | 86 (93%) | 0.975 |
| Manual aspiration thrombectomy (%) | 6 (13%) | 15 (16%) | 0.655 |
| Laboratory data (median IQR) | |||
| WBC (x103/L) | 11.1 [8.8–13.8] | 11.1 [8.4–11.1] | 0.974 |
| Creatinine (mg/L) | 0.99 [0.88–1.13] | 0.97 [0.81–1.42] | 0.836 |
| Peak CK-MB (ng/mL) | 187 [42–287] | 108 [49–222] | 0.070 |
| AUC-hsCRP (mg•day/L) | 153 [60–346] | 110 [51–224] | 0.192 |
| Echocardiographic data | |||
| LV Ejection Fraction, % (median, IQR) at baseline | 45 [40–54] | 53 [45–58] | 0.007 |
| LVEDV, ml, at baseline (median, IQR) | 98 [79–120] | 90 [73–115] | 0.379 |
| LVESV, ml, at baseline (median, IQR) | 54 [35–71] | 42 [32–60] | 0.121 |
| Interval change in LVEF %, (median, IQR) | +5% [−1 to 11] | +2% [−3 to +7] | 0.174 |
| Interval changes in LVEDV ml, (median, IQR) | +3 [−8 to +22] | +1 ml [−8 to +14] | 0.655 |
| Interval changes in LVESV, ml (median, IQR) | +2% [−3 to +7] | −0.3 [−14 to +10] | 0.947 |
| Medication at discharge | |||
| Beta-Blockers (%) | 39 (83%) | 82 (89%) | 0.307 |
| Aspirin (%) | 47 (100%) | 92 (100%) | 1 |
| ACEi/ARB (%) | 42 (89%) | 74 (80%) | 0.231 |
| Statin (%) | 46 (98%) | 91 (99%) | 1 |
| Spironolactone (%) | 4 (9%) | 4 (4%) | 0.443 |
| P2Y12 inhibitors (%) | 47 (100%) | 92 (100%) | 1 |
| Clopidogrel (%) | 24 (51%) | 32 (35%) | 0.064 |
| Prasugrel (%) | 10 (21%) | 24 (26%) | 0.532 |
| Ticagrelor (%) | 13 (28%) | 36 (39%) | 0.180 |
Abbreviations: ACEi/ARB: angiotensin converting enzymes inhibitor/ angiotensin II receptor blockers; BMI: body mass index; CABG: coronary artery bypass graft; CK-MB: Creatine kinase-MB; LV: left ventricle; LVEDV: left ventricle end-diastolic volume; LVESV: left ventricle end-systolic volume; hsCRP: high sensitivity C-reactive-protein; IQR: interquartile range; SD: standard deviation; TIMI: Thrombolysis in myocardial infarction; WBC: white blood cell count
Echocardiography data during the acute phase were available in 125 (91%) patients: 22 (18%) had LVEF<40% and 58 (46%) had LVEF <50%. Patients with anterior STEMI had significantly lower LVEF within 24 hours after enrollment compared to those with non-anterior STEMI (45% [40–54] vs 53% [45–58], p=0.007), with no significant differences in LVEDV (98 ml [79–120] vs 90 ml [73–115], p=0.379) or LVESV (54 ml [35–71] vs 42 ml [32–60]; p=0.121). Time from the initial echocardiogram to follow up echocardiogram was 336 (92–365) days. Interval change in LVEF was +5% [−1 to 11] in patients with anterior STEMI and +2% [−3 to +7] in those with non-anterior STEMI (p=0.174). Interval changes in LVEDV and LVESV were +3 ml [−8 to +22] and −0.3 ml [−14 to +10] in patients with anterior STEMI and +1 ml [−8 to +14], and −0.8 ml [−7 to +5], in those with non-anterior STEMI (p=0.655 and p=0.947, respectively) (Table 1).
LVEF data during the acute phase were available in 126 (91%) patients: 22 (18%) had LVEF<40% and 58 (46%) LVEF <40%. When comparing anterior vs non-anterior STEMI according to the treatment received (anakinra vs placebo), a significant difference in LVEF was observed across the four groups (p=0.035). No difference was observed in LVEF when comparing anakinra vs placebo in anterior STEMI (46% [39–52] vs 44 % [40–60], p=0.393) as well as in non-anterior STEMI (53% [45–59] vs 54% [43–56], p=0.622) (Table 2).
Table 2:
Characteristics of the patients according to STEMI location (anterior vs non anterior) and treatment (anakinra vs placebo)
| Anterior STEMI | Non anterior STEMI | ||||
|---|---|---|---|---|---|
| Placebo (n=17) | Anakinra (n=30) | Placebo (n=38) | Anakinra (n=54) | P value | |
| Clinical Characteristics | |||||
| Age (median, IQR) | 58 [52–63] | 54 [48–60] | 57 [50–65] | 56 [49–61] | 0.464 |
| Male (%) | 15 (88%) | 21 (70%) | 33 (87%) | 41(76%) | 0.254 |
| White (%) | 10 (59%) | 17 (58%) | 25 (66%) | 35 (65%) | 0.842 |
| BMI (median, IQR) | 29 [27–34] | 31 [25–34] | 29 [26–36] | 31 [25–34] | 0.888 |
| Diabetes mellitus (%) | 9 (53%) | 5 (17%) | 10 (26%) | 15 (28%) | 0.066 |
| Hypertension (%) | 12 (71%) | 16 (53%) | 25 (66%) | 39 (54%) | 0.442 |
| Tobacco use (%) | 10 (59%) | 21 (70%) | 19 (50%) | 30 (56%) | 0.409 |
| Dyslipidemia (%) | 7 (41%) | 15 (50%) | 18 (47%) | 31 (57%) | 0.625 |
| Previous history of CABG (%) | 1 (6%) | 0 (0%) | 1 (3%) | 4 (7%) | 0.397 |
| Chronic obstructive pulmonary disease (%) | 1 (6%) | 2 (7%) | 4 (11%) | 1 (2%) | 0.368 |
| Clinical presentation | |||||
| Thrombolysis (%) | 2 (12%) | 2 (7%) | 5 (13%) | 5 (9%) | 0.831 |
| Symptoms to balloon time (min) | 210 [99–339] | 129 [77–244] | 180 [120–377] | 203 [130–416] | 0.301 |
| Angiographic data | |||||
| TIMI flow 0/1 pre-PCI (%) | 15 (88%) | 27 (90%) | 28 (74%) | 47 (87%) | 0.218 |
| TIMI flow 3 post-PCI (%) | 16 (94%) | 29 (97%) | 37 (97%) | 51 (94%) | 0.204 |
| Coronary artery stenting (%) | 17 (100%) | 27 (90%) | 38 (100%) | 48 (89%) | 0.096 |
| Manual aspiration thrombectomy (%) | 1 (6%) | 5 (17%) | 9 (24%) | 6 (11%) | 0.831 |
| Laboratory data at baseline (median IQR) | |||||
| WBC (x103/L) | 13.9 [8.7–16.1] | 10.3 [8.4–10.3] | 10.5 [8.0–13.8] | 11.8 [9.0–14.2] | 0.070 |
| Peak CK-MB (ng/mL) | 143 [31–293] | 212 [89–260] | 94 [59–218] | 118 [40–223] | 0.360 |
| AUC-hsCRP (mg•day/L) | 310 [197–593] | 98 [42–196] | 184 [108–322] | 66 [41–138] | <0.001 |
| Echocardiographic data (median, IQR) | |||||
| LV Ejection Fraction, % at baseline | 44 [40–60] | 46 [39–52] | 54 [43–56] | 53 [45–59] | 0.035 |
| Interval change in LVEF, % | +2% [−6 to 9] | +5% [+1 to +12] | +2% [−4 to +7] | +1% [−2 to +7] | 0.229 |
| Interval changes in LVEDV, ml | +2.5 [−9 to +8] | +3 [−6 to +26] | −3.5 [−14 to +11] | +4 [−6 to +16] | 0.222 |
| Interval changes in LVESV, ml | +2 [−15; +13], | −1 [−14 to +10] | +3 [−11 to +3] | +1 [−7 to +6] | 0.665 |
| Medication at discharge | |||||
| Beta-Blockers (%) | 15 (88%) | 24 (80%) | 32 (84%) | 50 (93%) | 0.378 |
| Aspirin (%) | 17 (100%) | 30 (100%) | 38 (100%) | 53 (98%) | 0.663 |
| ACEi/ARB (%) | 14 (82%) | 26 (87%) | 33 (87%) | 43 (80%) | 0.771 |
| Statin (%) | 17 (100%) | 30 (100%) | 37 (97%) | 53 (98%) | 0.663 |
| P2Y12 inhibitors (%) | 17 (100%) | 30 (100%) | 38 (100%) | 54 (100%) | 1 |
Abbreviations: ACEi/ARB: angiotensin converting enzymes inhibitor/ angiotensin II receptor blockers; BMI: body mass index; CABG: coronary artery bypass graft; CK-MB: Creatine kinase-MB; LV: left ventricle; LVEDV: left ventricle end-diastolic volume; LVESV: left ventricle end-systolic volume; hsCRP: high sensitivity C-reactive-protein; IQR: interquartile range; SD: standard deviation; TIMI: Thrombolysis in myocardial infarction; WBC: white blood cell count
Matched echocardiography data were available in 97 (70%) of patients. When comparing anterior vs non-anterior STEMI according to the treatment received (anakinra vs placebo), there were no differences in interval changes in LVEF (p=0.229), LVEDV (p=0.222) and LVESV (p=0.665) across the groups. In patients with anterior STEMI no significant differences were observed when comparing anakinra vs placebo in interval changes in LVEF (+5% [+1 to +12] vs +2% [−6 to 9], p=0.182), LVEDV (+3 ml [−6 to +26] vs +2.5 ml [−9 to +8], p=0.604) and LVESV (−1 ml [−14 to +10] vs +2 ml [−15 to+13], p=0.774), nor in patients with non-anterior STEMI, with interval changes for anakinra and placebo of LVEF (+1% [−2 to +7] vs +2% [−4 to +7], p=0.914), LVEDV (+4 ml [−6 to +16] vs −3.5 ml [−14 to +11], p=0.115) and LVESV (1 ml [−7 to +6] vs 3 ml [−11 to +3], p=0.296) (Table 2).
Clinical follow-up was available for all patients with a median follow-up of 365 [240–365] days. The composite endpoint of death or new-onset HF occurred in 11 (23%) patients among those with anterior STEMI and in 12 (13%) patients among those with non-anterior STEMI (log-rank p value=0.131).
Of the 47 patients with anterior STEMI, 17 (36%) were in the placebo group and 30 (64%) in the anakinra group. We found a significant interaction between STEMI location (anterior vs non-anterior), treatment with anakinra and heart failure outcomes (log-rank p=0.006) (Figure 1). Anakinra significantly reduced the combined endpoint of death or new onset HF in patients with anterior STEMI (4 (13%) vs 7 (42%), log-rank p value=0.049). Of the 92 (64%) with non-anterior STEMI, 38 (41%) were in the placebo group and 54 (59%) in the anakinra group. Anakinra significantly reduced the combined endpoint of death or new onset HF in patients with non-anterior STEMI (3 [6%] vs 9 [24%], log-rank p value= 0.014) (Figure 1).
Figure 1.
Panel A: Kaplan-Meier curves for the incidence of the composite of all-cause death and new-onset HF with a comparison between groups by log-rank test in patients with anterior STEMI. Panel B: Kaplan-Meier curves for the incidence of the composite of all-cause death and new-onset HF with a comparison between groups by log-rank test in patients with non-anterior STEMI.
There were no differences in cardiovascular medications at discharges between the placebo and anakinra groups (Table 2).
Discussion
In this secondary analysis of the pooled data of three randomized clinical trials of IL-1 blockade with anakinra in STEMI patients, anakinra was associated with a lower incidence of HF at 1 year follow-up independent of anterior or non-anterior location and of changes in LVEF or LV volumes.
Patients with anterior STEMI represent a population characterized by a larger myocardial area at risk and greater left ventricular systolic dysfunction, factors associated with worse prognosis in patients with STEMI (20–21). Therefore patients with anterior STEMI are considered to be at higher risk of early in-hospital complications and long term adverse cardiovascular outcomes, especially HF (9–11). We defined anterior vs non anterior STEMI according to the involvement or not of the LAD artery as the culprit vessel, yet all patients met also anterior STEM based on classic ECG criteria.
In this cohort we found indeed that patients with anterior STEMI had a significant worse LV systolic function and a trend toward greater infarct size compared to those with non-anterior STEMI, thus confirming prior findings. Of note, we included a diverse population from a large urban hospital in central Virginia, USA, including a significant proportion of black patients, often underrepresented in the clinical trials (22).
In patients with STEMI, we recently reported that treatment with anakinra for 14 days significantly reduced the incidence of HF events at follow-up, a protective effect that was independent of whether they had reduced or preserved LVEF at admission (18). Of note, we also showed that anakinra exerts beneficial effects on HF outcomes independently of significant changes in infarct size and measures of left ventricular cardiac remodeling (18,23).
In line with the previous reports, we show that the benefit of anakinra on HF outcomes is independent of whether patients have anterior or non-anterior STEMI and independent of changes in LVEF and LV volumes at follow-up.
The improvements in STEMI management have led to a significant reduction of the incidence and severity of systolic dysfunction and adverse cardiac remodeling (2,4,5,24,25). A significant number of STEMI survivors, however, continue to experience HF, independent of cardiac remodeling and reduced LVEF, displaying a phenotype of preserved EF (HFpEF) characterize by reduced cardiac reserve and impaired cardiorespiratory fitness (2,4,5,24–27). In the pooled data analysis of three VCUART clinical trials, 8 (50%) of the patients had a reduced LVEF at follow up (LVEF <40%), whereas 4 (25%) had LVEF 40–50% and 4 (25%) had HFpEF (LVEF >50%) (23). The inflammatory response during STEMI may modulate the response of the cardiomyocytes and other cells during the initial ischemic injury. IL-1 interferes with the intrinsic property of cardiomyocytes to contract (inotropy) and to relax (lusitropy) leading to the impariement of systolic and diastolic cardiac reserve (28).
IL-1 blocking with anakinra may interfere with one of these mechanisms leading to the improvement of cardiorespiratory fitness and prevention of HF hospitalizations (14,29,30), independently of the infarct size, the the severity of systolic dyfunction, STEMI location and changes in LV volumes.
This study has some limitations. This is a post-hoc analysis of three randomized control trials with limited power for detecting differences in clinical outcomes. However, the similar design, inclusion and exclusion criteria of the three studies allowed the pooled data analysis.
Conclusion
In conclusion, anakinra is associated with a reduction of heart failure events in patients with STEMI, irrespective of anterior or non-anterior location, and of changes in LVEF or LV volumes.
Funding:
The VCUART2 study was supported by an American Heart Association Scientist Development grant 10SDG 3030051 and a Presidential Research Incentive Program of the Virginia Commonwealth University to Dr. Abbate and by an Institutional National Institute of Health K12 award KL2RR031989 to Dr. Van Tassell. The VCUART3 study was supported by a grant from the National Institutes of Health (1R34HL121402-01) to Dr. Abbate and Dr. Van Tassell. Swedish Orphan Biovitrum provided anakinra and matching placebo for VCUART3.
Footnotes
Publisher's Disclaimer: Disclosures: Dr Abbate and Dr Van Tassell have served as consultants to Swedish Orphan Biovitrum LLC in the past. The remaining authors have no disclosures to report. Dr. Biondi-Zoccai has consulted for Cardionovum, CrannMedical, InnovHeart, Meditrial, Opsens Medical, and Replycare.
References
- 1.Ezekowitz JA, Kaul P, Bakal JA, Armstrong PW, Welsh RC, McAlister FA. Declining in-hospital mortality and increasing heart failure incidence in elderly patients with first myocardial infarction. J Am Coll Cardiol. 2009;53(1):13–20. [DOI] [PubMed] [Google Scholar]
- 2.Cung TT, Morel O, Cayla G, Rioufol G, Garcia-Dorado D, Angoulvant D, Bonnefoy-Cudraz E, Guérin P, Elbaz M, Delarche N, Coste P, Vanzetto G, Metge M, Aupetit JF, Jouve B, Motreff P, Tron C, Labeque JN, Steg PG, Cottin Y, Range G, Clerc J, Claeys MJ, Coussement P, Prunier F, Moulin F, Roth O, Belle L, Dubois P, Barragan P, Gilard M, Piot C, Colin P, De Poli F, Morice MC, Ider O, Dubois-Randé JL, Unterseeh T, Le Breton H, Béard T, Blanchard D, Grollier G, Malquarti V, Staat P, Sudre A, Elmer E, Hansson MJ, Bergerot C, Boussaha I, Jossan C, Derumeaux G, Mewton N, Ovize M. Cyclosporine before PCI in Patients with Acute Myocardial Infarction. N Engl J Med. 2015. Sep 10;373(11):1021–31. [DOI] [PubMed] [Google Scholar]
- 3.Chen J, Hsieh AF, Dharmarajan K, Masoudi FA, Krumholz HM. National trends in heart failure hospitalization after acute myocardial infarction for Medicare beneficiaries: 1998–2010. Circulation. 2013;128(24):2577–2584. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Mewton N, Roubille F, Bresson D, Prieur C, Bouleti C, Bochaton T, Ivanes F, Dubreuil O, Biere L, Hayek A, Derimay F, Akodad M, Alos B, Haider L, El Jonhy N, Daw R, De Bourguignon C, Dhelens C, Finet G, Bonnefoy-Cudraz E, Bidaux G, Boutitie F, Maucort-Boulch D, Croisille P, Rioufol G, Prunier F, Angoulvant D. Effect of Colchicine on Myocardial Injury in Acute Myocardial Infarction. Circulation. 2021. Sep 14;144(11):859–869. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Cavender MA, O’Donoghue M, Abbate A, Aylward P, Fox KAA, Glaser RX, Park JG, Lopez-Sendon J, Steg PG, Sabatine MS, Morrow DA. Inhibition of p38 MAP Kinase in Patients with ST-Elevation Myocardial Infarction - Findings from the LATITUDE TIMI 60 Trial. Am Heart J. 2021. Sep 8:S0002–8703(21)00229–5 [DOI] [PubMed] [Google Scholar]
- 6.Toldo S, Abbate A. The NLRP3 inflammasome in acute myocardial infarction. Nat Rev Cardiol. 2018;15(4):203–214. [DOI] [PubMed] [Google Scholar]
- 7.Seropian IM, Sonnino C, Van Tassell BW, Biasucci LM, Abbate A. Inflammatory markers in ST-elevation acute myocardial infarction. Eur Heart J Acute Cardiovasc Care. 2016;5(4):382–395. [DOI] [PubMed] [Google Scholar]
- 8.Seropian IM, Toldo S, Van Tassell BW, Abbate A. Anti-inflammatory strategies for ventricular remodeling following ST-segment elevation acute myocardial infarction. J Am Coll Cardiol. 2014;63(16):1593–1603. [DOI] [PubMed] [Google Scholar]
- 9.Masci PG, Ganame J, Francone M, et al. Relationship between location and size of myocardial infarction and their reciprocal influences on post-infarction left ventricular remodelling. Eur Heart J. 2011;32(13):1640–1648. [DOI] [PubMed] [Google Scholar]
- 10.Del Buono MG, Montone RA, Rinaldi R, et al. Clinical predictors and prognostic role of high Killip class in patients with a first episode of anterior ST-segment elevation acute myocardial infarction. J Cardiovasc Med (Hagerstown). 2021;22(7):530–538. [DOI] [PubMed] [Google Scholar]
- 11.Stone PH, Raabe DS, Jaffe AS, et al. Prognostic significance of location and type of myocardial infarction: independent adverse outcome associated with anterior location. J Am Coll Cardiol. 1988;11(3):453–463. [DOI] [PubMed] [Google Scholar]
- 12.Abbate A, Toldo S, Marchetti C, Kron J, Van Tassell BW, Dinarello CA. Interleukin-1 and the Inflammasome as Therapeutic Targets in Cardiovascular Disease. Circ Res. 2020;126(9):1260–1280. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.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; CANTOS Trial Group. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017. Sep 21;377(12):1119–1131 [DOI] [PubMed] [Google Scholar]
- 14.Everett BM, Cornel JH, Lainscak M, Anker SD, Abbate A, Thuren T, Libby P, Glynn RJ, Ridker PM. Anti-Inflammatory Therapy With Canakinumab for the Prevention of Hospitalization for Heart Failure. Circulation. 2019. Mar 5;139(10):1289–1299. [DOI] [PubMed] [Google Scholar]
- 15.Abbate A, Kontos MC, Grizzard JD, Biondi-Zoccai GG, Van Tassell BW, Robati R, Roach LM, Arena RA, Roberts CS, Varma A, Gelwix CC, Salloum FN, Hastillo A, Dinarello CA, Vetrovec GW; VCU-ART Investigators. Interleukin-1 blockade with anakinra to prevent adverse cardiac remodeling after acute myocardial infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot study). Am J Cardiol. 2010. May 15;105(10):1371–1377.e1. [DOI] [PubMed] [Google Scholar]
- 16.Abbate A, Van Tassell BW, Biondi-Zoccai G, Kontos MC, Grizzard JD, Spillman DW, Oddi C, Roberts CS, Melchior RD, Mueller GH, Abouzaki NA, Rengel LR, Varma A, Gambill ML, Falcao RA, Voelkel NF, Dinarello CA, Vetrovec GW. Effects of interleukin-1 blockade with anakinra on adverse cardiac remodeling and heart failure after acute myocardial infarction [from the Virginia Commonwealth University-Anakinra Remodeling Trial (2) (VCU-ART2) pilot study]. Am J Cardiol. 2013. May 15;111(10):1394–400 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Abbate A, Kontos MC, Abouzaki NA, Melchior RD, Thomas C, Van Tassell BW, Oddi C, Carbone S, Trankle CR, Roberts CS, Mueller GH, Gambill ML, Christopher S, Markley R, Vetrovec GW, Dinarello CA, Biondi-Zoccai G. Comparative safety of interleukin-1 blockade with anakinra in patients with ST-segment elevation acute myocardial infarction (from the VCU-ART and VCU-ART2 pilot studies). Am J Cardiol. 2015. Feb 1;115(3):288–92. [DOI] [PubMed] [Google Scholar]
- 18.Abbate A, Trankle CR, Buckley LF, Lipinski MJ, Appleton D, Kadariya D, Canada JM, Carbone S, Roberts CS, Abouzaki N, Melchior R, Christopher S, Turlington J, Mueller G, Garnett J, Thomas C, Markley R, Wohlford GF, Puckett L, Medina de Chazal H, Chiabrando JG, Bressi E, Del Buono MG, Schatz A, Vo C, Dixon DL, Biondi-Zoccai GG, Kontos MC, Van Tassell BW. Interleukin-1 Blockade Inhibits the Acute Inflammatory Response in Patients With ST-Segment-Elevation Myocardial Infarction. J Am Heart Assoc. 2020. Mar 3;9(5):e014941. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Eapen ZJ, Tang WH, Felker GM, et al. Defining heart failure end points in ST-segment elevation myocardial infarction trials: integrating past experiences to chart a path forward. Circ Cardiovasc Qual Outcomes. 2012;5(4):594–600. [DOI] [PubMed] [Google Scholar]
- 20.Sutton NR, Li S, Thomas L, Wang TY, de Lemos JA, Enriquez JR, Shah RU, Fonarow GC. The association of left ventricular ejection fraction with clinical outcomes after myocardial infarction: Findings from the Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry-Get With the Guidelines (GWTG) Medicare-linked database. Am Heart J. 2016. Aug;178:65–73. [DOI] [PubMed] [Google Scholar]
- 21.Stone GW, Selker HP, Thiele H, Patel MR, Udelson JE, Ohman EM, Maehara A, Eitel I, Granger CB, Jenkins PL, Nichols M, Ben-Yehuda O. Relationship Between Infarct Size and Outcomes Following Primary PCI: Patient-Level Analysis From 10 Randomized Trials. J Am Coll Cardiol. 2016. Apr 12;67(14):1674–83 [DOI] [PubMed] [Google Scholar]
- 22.Ma MA, Gutiérrez DE, Frausto JM, Al-Delaimy WK. Minority Representation in Clinical Trials in the United States: Trends Over the Past 25 Years. Mayo Clin Proc. 2021;96(1):264–266. doi: 10.1016/j.mayocp.2020.10.027 [DOI] [PubMed] [Google Scholar]
- 23.Abbate A, Wohlford GF, Del Buono MG, et al. Interleukin-1 blockade with Anakinra and heart failure following ST-segment elevation myocardial infarction: results from a pooled analysis of the VCUART clinical trials [published online ahead of print, 2021 Oct 7]. Eur Heart J Cardiovasc Pharmacother. 2021;pvab075. doi: 10.1093/ehjcvp/pvab075. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Bulluck H, Carberry J, Carrick D, et al. Redefining Adverse and Reverse Left Ventricular Remodeling by Cardiovascular Magnetic Resonance Following ST-Segment-Elevation Myocardial Infarction and Their Implications on Long-Term Prognosis. Circ Cardiovasc Imaging. 2020;13(7):e009937. [DOI] [PubMed] [Google Scholar]
- 25.Rodriguez-Palomares JF, Gavara J, Ferreira-González I, et al. Prognostic Value of Initial Left Ventricular Remodeling in Patients With Reperfused STEMI. JACC Cardiovasc Imaging. 2019;12(12):2445–2456. [DOI] [PubMed] [Google Scholar]
- 26.Del Buono MG, Arena R, Borlaug BA, et al. Exercise Intolerance in Patients With Heart Failure: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73(17):2209–2225. [DOI] [PubMed] [Google Scholar]
- 27.Del Buono MG, Iannaccone G, Scacciavillani R, et al. Heart failure with preserved ejection fraction diagnosis and treatment: An updated review of the evidence. Prog Cardiovasc Dis. 2020;63(5):570–584. [DOI] [PubMed] [Google Scholar]
- 28.Buckley LF, Abbate A. Interleukin-1 blockade in cardiovascular diseases: a clinical update. Eur Heart J. 2018;39(22):2063–2069. [DOI] [PubMed] [Google Scholar]
- 29.Van Tassell BW, Canada J, Carbone S, et al. Interleukin-1 Blockade in Recently Decompensated Systolic Heart Failure: Results From REDHART (Recently Decompensated Heart Failure Anakinra Response Trial). Circ Heart Fail. 2017;10(11):e004373. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Van Tassell BW, Trankle CR, Canada JM, et al. IL-1 Blockade in Patients With Heart Failure With Preserved Ejection Fraction. Circ Heart Fail. 2018;11(8):e005036. [DOI] [PMC free article] [PubMed] [Google Scholar]