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THE IMPORTANCE OF PUBLISHING NEGATIVE FINDINGS Rolofylline, an Adenosine A1 – Receptor Antagonist, in Acute Heart Failure Barry M. Massie et al The New England Journal of Medicine October 2010 Michelle Aukland Why an Adenosine Receptor A1 Antagonist? • Adenosine acts on A1 receptors in the afferent arterioles, reducing renal blood flow and GFR • Adenosine stimulates absorption of sodium • A1 antagonists may preserve the GFR, enhance sodium excretion and improve diuretic responsiveness • Modlinger, Welch. Adenosine A1 receptor antagonists and the kidney. Curr opin Nephrol Hypertens. 2003 Sep; 12(5): 497-502 Why was the study done? • The PROTECT phase 2 pilot study • Rolofylline administered at 10, 20, 30mg daily for up to 3 days • N= 301 • Patients hospitalised with acute heart failure, underlying renal dysfunction and fluid overload • RESULTS – compared with placebo, the 30mg dose provided greater relief of dyspneoa, less worsening of renal failure, fewer deaths or re-admissions for heart/renal failure • Cotter, Dittrich, Weatherly et al. The PROTECT pilot study: a randomized, placebo controlled, dose-finding study of the adenosine A1 receptor antagonist rolofylline in patients with acute heart failure and renal impairment. J Card Fail 2008; 14:631-40. Methods • Multicentre, double-blind, placebo controlled trial • <24 hours presentation of acute heart failure with impaired renal function • N= 2033 • 2:1 daily rolofylline 30mg iv : placebo • Primary end point – treatment success, failure, no change • Secondary end point – persistent renal impairment, 60 day rate of death or re-admission for cardiovascular/renal causes • Sponsored by NovaCardia Study Patients • Persistent dyspneoa with minimal activity • Estimated creatinine clearance of 2080ml/minute • BNP >500pg per ml or N-terminal pro-BNP >2000pg per ml • Ongoing iv loop diuretic therapy • Enrolment < 24 hours after admission • EXCLUDED – hx or predisposing factors for seizures Study procedures • 30mg Rolofylline or placebo was given as a 4 hour IV infusion daily for up to 3 days • Signs & symptoms of heart failure were evaluated initially, daily to discharge or day 6, and on days 7 and 14. • Likert scale -3 to +3 used to record change in dyspnoea and general well-being • Creatinine levels recorded at same points Study Primary End Points • Success Moderate/marked improvement in dyspneoa at 24 and 48 hours • Failure Death or re-admission for heart failure by day 7 Worsening symptoms of HF >24 after drug started Persistent worsening renal function • Unchanged – neither of above criteria met Secondary Outcomes 1. Proportion of patients with persistent renal failure (increase in creatinine > 26.5umol/l by day 7, confirmed at day 14, or filtration/dialysis initiated by day 7) 2. Death or rehospitalisation for renal or cardiovascular causes by day 60 Results – distribution of primary endpoints Cumulative risk of death or readmission for cardiovascular or renal causes Conclusions • Rolofylline did not improve primary outcomes or improve renal function or 60-day outcomes • Rolofylline was also associated with a higher incidence of seizures and stroke • Development of rolofylline was terminated in 2009 • Robust study Why did the results not replicate those in the pilot study? • Different inclusion criteria – pilot study did not use increase in BNP • Different assessment of successful treatment in pilot trial – physician directed switch from iv to oral diuretic • Change in definition of persistent renal impairment (Pilot study – increase of creatinine by 26.5umol from baseline to day 7) • Small treatment groups in each dose group Why is it important to publish negative studies? Avoid publication bias • Journals prefer to publish new ‘exciting’ findings • Business model of journals and need to sell subscriptions - POSITIVE papers • Some researchers more interested in how things work rather than learning that hypotheses were incorrect? • Researchers prefer submitting to higher profile journals • May reveal flaws in methods • Drug companies withhold negative results • Focuses future research