Attenuation of systemic inflammatory response in acute decompensated HF

Van Tassell BW, Abouzaki NA, Erdle CO, et al.
Journal of Cardiovascular Pharmacology 2016; published online ahead of print

Background

The rates of acute decompensated heart failure (ADHF) requiring hospitalisation have tripled over the past 25 years, and ADHF leads to [1-3]:

• mortality of 3-4% during admission
• rehospitalisation of 50%
• increased HF morbidity and mortality after discharge

Existing evidence suggests that inflammation is present in ADHF [4,5].
In this randomised, double-blinded, placebo-controlled study, it was investigated whether IL-1 blockage with anakinra can attenuate the acute inflammatory response in patients with ADHF. Interleukin-1 (IL-1) is an inflammatory cytokine that is markedly elevated during ADHF as measured by the surrogate biomarkers C-reactive protein and IL-6, and is sufficient to cause cardiac dysfunction in cellular and animal models of HF [6,7].
30 patients with ADHF, reduced left ventricular ejection fraction (LVEF<40%), and elevated C reactive protein (CRP) levels (≥5 mg/L) were randomized to either anakinra 100 mg twice daily for 3 days followed by once daily for 11 days or matching placebo, in a 1:1 double blinded fashion. Daily CRP plasma levels were measured using a high-sensitivity assay during hospitalization and then again at 14 days and the area-under-the-curve (AUC) and interval changes (delta) were evaluated.
Fourteen patients in the anakinra group (93%) and 13 patients in the placebo group (87%) completed the study protocol through the first 72 hours (or discharge) and were converted to once-daily dosing.
A total of 9 patients in the anakinra group (60%) and 8 patients in the placebo group (53%) returned to clinic for the 14-day clinical follow-up.

Main results

• CRP values during the first 72 hours of treatment vs baseline:

- patients randomised to anakinra: -61.0%; 95% CI: -71.2% to -51.5%; P=0.002 (and P=0.004 vs placebo)
- patients randomised to placebo: -6.0%; 95% CI: -32.6% to 54.5%; P=0.88

• Patients on anakinra were more likely to achieve a 50% reduction in CRP within 72 hours: 75% vs 17%, P=0.008
• CRP values after 14 days of treatment vs baseline:

- patients randomised to anakinra: -98%; 95% CI: -99% to -90%; P<0.01
- patients randomised to placebo: -85%; 95% CI: -92% to -56%; P<0.01

• Patients receiving anakinra were more likely to achieve a “normalized” CRP value (<2 mg/L) at 14 days (78% vs 25%, P=0.040)
• Treatment with anakinra produced significant reductions in IL-6:  

- after 3 days: 0.79; 95% CI: 0.59 - 2.20; P<0.05
- after 14 days: 0.44; 95% CI: 0.30 - 0.90; P<0.05

• Treatment with anakinra was well tolerated

Conclusion

In patients with ADHF, 14 days of IL-1 blockade with anakinra reduced the systemic inflammatory response, and was well tolerated. These results provide confirmatory evidence that IL-1 drives the systemic inflammatory response during ADHF, and mediates the IL-6 and CRP response in this setting.

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References

1. Gwadry-Sridhar FH, Flintoft V, Lee DS, et al. A systematic review and meta-analysis of studies comparing readmission rates and mortality rates in patients with heart failure. Arch Intern Med 2004;164:2315-20
2. Cleland JG, Coletta AP, Yassin A, et al. Clinical trials update from the European Society of Cardiology Meeting 2009: AAA, RELY, PROTECT, ACTIVE-I, European CRT survey, German pre-SCD II registry, and MADIT-CRT. Eur J Heart Fail 2009;11:1214-9
3. Cleland JG, Freemantle N, Coletta AP, et al. Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE. Eur J Heart Fail 2006;8:105-10
4. Deswal A, Petersen NJ, Feldman AM, et al. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation 2001;103:2055-9
5. Long CS. The role of interleukin-1 in the failing heart. Heart Fail Rev 2001;6:81-94
6. Van Tassell BW, Arena RA, Toldo S, et al. Enhanced Interleukin-1 activity contributes to exercise intolerance in patients with systolic heart failure. PLoS One 2012;7:e33438
7. Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 2011;117:3720-32.3083294