THE IMPORTANCE OF PUBLISHING NEGATIVE FINDINGS

Rolofylline, an Adenosine A1 – Receptor Antagonist, in Acute Heart Failure

Barry M. Massie et alThe 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

20-80ml/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