Editorial
How to RECOVER from RENAISSANCE? The significance of the results of RECOVER, RENAISSANCE, RENEWAL and ATTACH

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Abstract

Two trial programmes testing an anti-cytokine medication in chronic heart failure (CHF) have been halted. In the RENAISSANCE and RECOVER trials (the combined analysis being termed RENEWAL), 2048 CHF patients were randomised to placebo or one of 3 doses of etanercept, a fusion protein directed against TNF. Within RENAISSANCE and RECOVER a clinical composite score was used to assess the clinical effects at 24 weeks (primary endpoint: alpha 0.04). Overall, the number of patients who were classified to have during the trial “improved”, remained “unchanged” or “worsened” was similar for patients on placebo or any dose of etanercept (RENAISSANCE: p=0.17, RECOVER: p=0.34). In RENEWAL (combined analysis of medium and high dose etanercept vs. placebo), the primary endpoint (death or CHF hospitalisation, alpha 0.01) was not different between etanercept and placebo (RR 1.10, 95%CI 0.91 to 1.33, p=0.33). In RENEWAL, the secondary endpoint (death for any cause) was not different between etanercept and placebo (RR 1.13, 95%CI 0.86 to 1.50, p=0.39). ATTACH was a phase II, multicentre, randomised, double-blind, placebo-controlled pilot trial that aimed to evaluate the effects of infliximab (an antibody against TNF given in 2 different doses) in 150 CHF patients with stable NYHA class III or IV (in NYHA IV: <10%). In the placebo group (n=49), none of the patients died during 28 weeks of follow-up. At 14 (28) weeks, the endpoint of death or hospitalisation was reached in 2 (5) patients on placebo, in 2 (4) patients in the medium dose (5 mg/kg), and in 8 (13) patients in the high dose (10 mg/kg) of infliximab. During follow-up, compared to placebo the hazard to reach this endpoint was similar in the medium dose group (RR 0.80, 95%CI 0.22–2.99), but increased in the high dose group (RR 2.84, 95%CI 1.01–7.97, p<0.05). Conclusion: At the respective lower doses there was no safety issue with regards to the use of either infliximab or etanercept. High dose anti-TNF therapy may not be useful in CHF patients, but the situation in lower doses and in patients with documented inflammatory/metabolic problems or in cardiac cachexia has not yet been adequately assessed.

Section snippets

The background in CHF

Plasma levels of inflammatory cytokines (including TNF) are raised in CHF patients, particularly in those in NYHA IV, cardiogenic shock or with cardiac cachexia (reviewed in [9]). Inflammatory cytokines are produced in the heart and can contribute to cardiac dysfunction [10], [11], they directly relate to poor peripheral perfusion [12], body composition [13], and weight changes [14], and the higher the plasma levels of parameters of inflammatory immune activation (like TNF, soluble TNF

Etanercept and infliximab in other disease states

Etanercept is a TNF receptor fusion protein [21], [22] which can be administered sub-cutaneously. The extracellular domain of the human p75 TNF receptor is fused to the Fc region of human IgG1. Infliximab is a chimeric (mouse/human) IgG1 monoclonal antibody that binds to both soluble and transmembrane TNF with high specificity and affinity [24]. Infliximab is given by intravenous application.

Anti-TNF therapies have recently been introduced for the management of rheumatoid arthritis and Crohn’s

The new studies: RENAISSANCE, RECOVER, RENEWAL, ATTACH

On this background, in 1996/1997 the RENAISSANCE, RECOVER and RENEWAL studies were designed. ATTACH followed somewhat later. In Oslo, Milton Packer stated that ATTACH was designed to be a pilot study for a subsequent morbidity/mortality study that would have been similar to the studies on etanercept [5]. The studies’ trial design, baseline patient characteristics and some of the main results are presented in Fig. 1, Fig. 2, and Table 1, Table 2, Table 3, Table 4, Table 5.

The etanercept studies

The king is dead – long live the king !?

Is the cytokine hypothesis [10] dead? We think reports of its death may be premature. Many, of course, have been discouraged by the results as documented above. We think they are not entirely surprising [39]. The cytokine hypothesis may not yet have been tested adequately in the right patients at the right doses !

The inclusion criteria of both trials were broad. In RENAISSANCE/RECOVER patients in NYHA II were allowed into the study. In ATTACH, the very low mortality in the placebo group (2% at

Acknowledgements

SDA is supported with the Vandervell Fellowship (London, UK) and a grant for “Applied Cachexia Research” by the Charité Medical School, Berlin, Germany. AJSC is supported by the Viscount Royston Trust, the British Heart Foundation and the Robert Luff Foundation.

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