Methods

The designs of the individual studies are registered in www.clinicaltrials.gov ( NCT00789724 and NCT01175018 ). The studies had identical inclusion criteria, briefly summarized as age >18 years, acute (<24 hours) onset of chest pain, ST-segment elevation, and planned or completed angiography for urgent percutaneous coronary intervention (PCI), and exclusion criteria, including cardiac arrest, unsuccessful PCI, hemodynamic instability, previous Q-wave infarction or preexisting severe congestive heart and/or severe left ventricular (LV) dysfunction (left ventricular ejection fraction [LVEF] <20%), severe aortic or mitral valve disease, contraindications to magnetic resonance imaging, pregnancy, chronic infections, autoinflammatory or autoimmune disease, or cancer.

All patients were enrolled at the Virginia Commonwealth University, VCU Pauley Heart Center, from November 2008 to February 2009 in VCU-ART or from September 2010 to May 2012 in VCU-ART2. The patients were randomly assigned 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, in a double-blinded fashion. Clinical follow-up was performed during hospitalization and then at weeks 2 and 12, with clinical event adjudication at the end of the individual study.

For the purpose of this patient-level pooled analysis, an extended follow-up was completed in all patients using existing clinical data with the longest available follow-up. Clinical events occurring before the 12-week follow-up have been reported in the original publications. Clinical events after the first 12 weeks were reviewed and adjudicated by 2 investigators who were unaware of treatment allocation in the study and based on the documentation available in the chart, and consensus was needed for all determinations. End points included death, death due to cardiac cause, AMI (defined as type 1, according to the universal classification of AMI ), stroke (ischemic and hemorrhagic), unstable angina (defined as recurrence or worsening angina leading to hospitalization and/or need for urgent revascularization), new-onset heart failure (defined as new-onset dyspnea associated with clinical, imaging, or laboratory evidence of congestion, and requiring the use of loop diuretics).

Data are presented as number of events and percentage or as median and interquartile range for continuous variables. Kaplan-Meier curves for survival and event-free survival were constructed, compared Cox proportional hazard analysis stratified per study, and reported hazard ratio with 95% confidence interval. Unadjusted p values are reported throughout, with statistical significance set at the 2-tailed 0.05 level. The analyses were completed using SPSS, version 19.0 (IBM, Armonk, New York) and STATA 13 (StataCorp, College Station, Texas).

Results

The pooled analysis included 40 patients randomized 1:1 to anakinra or placebo. The clinical characteristics of the individual patients are included in the original reports. Tables 1 and 2 list the clinical characteristics according to group allocation. Supplementary Table 1 lists medical therapy at the time of hospital discharge in each group.

Median follow-up was 28 months (interquartile range 3 to 38 months). All patients were evaluated at completion of the 2-week investigational treatment. Five patients, 3 (15%) in the placebo group and 2 (10%) in the anakinra group, had an adverse event requiring discontinuation of treatment that included a diagnosis of sepsis in 4 cases (2 in each group) and need for urgent cardiac surgery in 1 patient in the placebo group. Injection site reactions were numerically more common in the anakinra group (5, 25%) versus placebo (2, 10%; p = 0.21) but did not lead to interruption of treatment.

Adverse cardiovascular events occurred in 16 patients, 9 (45%) in the placebo group and 7 (35%) in the anakinra group ( Table 3 ). One patient (5%) in the placebo group died. Two patients, 1 (5%) in the placebo and 1 (5%) in the anakinra group had recurrent STEMI, 2 patients (10%) in the anakinra group had NSTEMI, and 1 patient (5%) in the placebo group had an ischemic stroke. Five patients, of whom 3 (15%) in the placebo and 2 (10%) in the anakinra group, had unstable angina requiring hospitalization, 2 of whom, 1 in each group, required repeated revascularization.

Table 3

Adverse cardiovascular events

Patients with events	Placebo									Anakinra
	1	2	3	4	5	6	7	8	9	1	2	3	4	5	6	7
Death (cardiac death)				✓
Acute coronary syndromes	✓		✓		✓		✓			✓	✓	✓		✓	✓
– STEMI							✓				✓
– NSTEMI										✓				✓
– Unstable Angina	✓		✓		✓							✓			✓
– Revascularization					✓		✓				✓	✓		✓
Heart failure	✓	✓	✓	✓	✓	✓	✓	✓	✓				✓			✓
– LVEF <40%			✓	✓			✓	✓	✓				✓
– NYHA III/IV	✓	✓	✓	✓	✓	✓	✓	✓	✓				✓			✓
– BNP >100 pg/ml		✓	✓	✓	✓	✓	✓	✓	✓				✓			✓
– LVEDP >16 mm Hg	✓			✓	✓				✓				✓
– Hospitalization				✓	✓
Stroke (ischemic)			✓

The Table shows 22 events occurring in 16 patients, 9 in the placebo group and 7 in the anakinra group. LVEF, NYHA class, BNP and LVEDP values refer to the time when the diagnosis of heart failure was diagnosed, which varies between patients.

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