National Horizon Scanning Centre August 2008

National Horizon Scanning Centre

Rolofylline for acute heart failure

August 2008

This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes.

The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research

August 2008 National Horizon Scanning Centre News on emerging technologies in healthcare Rolofylline for acute heart failure

Target group • Acute heart failure (AHF) – hospitalised patients.

Background Tubuloglomerular feedback (TGF), the body’s response to avoid excess fluid loss is activated when elevated sodium concentrations in the distal renal tubules are detected. TGF promotes the release of adenosine which binds to A1 receptors causing vasoconstriction of the afferent arteriole, decreased renal blood flow (RBF) and enhanced sodium reabsorption by the proximal tubule. This action results in a decrease in glomerular filtration rate (GFR), diminished renal function, and sodium and water retention.

TGF is proposed as a contributing factor to diuretic resistance that occurs in some patients with heart failure. Higher doses of diuretics are required to overcome the decreased natriuresis and reduced RBF induced by TGF. This action creates a vicious circle of worsening renal function and diminished diuretic effectiveness. Worsening renal function is a predictor of poor outcomes in patients with AHF. If it occurs during hospitalisation, it is often associated with increased mortality, morbidity, increased length of stay, hospital re-admission and increased post-discharge death1,2.

Technology description Rolofylline (MK-7418, KW-3902) is a selective adenosine A1 receptor antagonist that blocks adenosine-mediated vasoconstriction of afferent arterioles in the kidney thereby maintaining GFR. It also inhibits sodium reabsorption in the proximal tubule and enhances diuresis. Rolofylline is intended to be used in addition to loop diuretics. It is administered intravenously (IV), 30mg over 4 hours daily for up to 3 days.

Innovation and/or advantages Rolofylline is the first in a novel class of treatments for AHF. Potential benefits include shorter hospital stays in higher dependency areas, lower doses of diuretics and possibly fewer re-admissions or shorter overall stays.

Developer Merck Sharp & Dohme Ltd.

Availability, launch or marketing dates, and licensing plans: In phase III clinical trials. NHS or Government priority area: This topic is relevant to the National Service Framework for Coronary Heart Disease (2000).

Relevant guidance • NICE technology appraisal in development. Nesiritide for acute decompensated heart failure. Publication date to be confirmed3. • NICE technology appraisal. Cardiac resynchronisation therapy for the treatment of heart failure4.

2 August 2008 National Horizon Scanning Centre News on emerging technologies in healthcare • NICE clinical guideline. Management of chronic heart failure in adults in primary and secondary care. Issued July 2003. Guideline warrants a partial update after March 2008 review5.

• SIGN. Management of chronic heart failure. 20076. • The European Society of Cardiology. Guidelines for the diagnosis and treatment of acute and chronic heart failure. 20087.

Clinical need and burden of disease The number of patients on Quality and Outcomes Framework (QOF) disease registers with heart failure was 419,856 in the period 2006-2007, an unadjusted prevalence of 0.8% of all patients registered with a general practitioner in England8. The quality of life experienced by people with heart failure is generally worse than that for people with other chronic conditions, such as arthritis or chronic lung disease9. Prognosis is poor with almost 40% of those diagnosed dying within a year. There were 8,109 registered deaths from heart failure in England and Wales in 2006, 97% of these being in the 65 and over age group10.

In 2005-2006 there were 63,306 admissions to hospital with a primary diagnosis of heart failure and 106,500 finished consultant episodes (ICD I50)11. Of the admissions 57,080 (90%) were emergencies – 1.2% of all emergency medical admissions to hospital. Heart failure accounted for 844,215 in-patient bed days – 1.6% of all NHS in-patient bed days.

Existing treatments and potential comparators Treatment options for AHF aim to improve symptoms (dyspnoea and/or fatigue) and to stabilise the haemodynamic condition7. Options include: • Oxygen and ventilator assistance (Intensive Care Therapy). • Morphine for severe dyspnoea, agitation or pain. • Diuretics and loop diuretics e.g. furosemide, bumetandine, torasemide, thiazides • Vasodilators e.g. nitrates, sodium nitroprusside, neseritide. • Inotropic agents e.g. dopamine, dobutamine, levosimendan.

Efficacy and safety

Trial code, PROTECT – pilot12: rolofylline vs. ADHF Protocol13: rolofylline vs. placebo; name, phase placebo; phase III. phase II. Sponsor Merck & Co., Inc. Merck & Co., Inc. Status Published Published Location USA USA Design Randomised, placebo-controlled, dose- Randomised, double-blind, placebo- ranging. controlled. Participants n=301; adults; at least 14-day history of n= 146; adults, hospitalised, New York in trial AHF, continued need for diuretics, renal Heart Association (NYHA) class II-IV, impairment (creatinine clearance 20- renal impairment (creatinine clearance 20- 80mL/min) and systolic blood 80mL/min). pressure>95 mmHg. Randomised to placebo, rolofylline 2.5mg, Randomised to placebo (n=78), 15mg, 30mg or 60mg; once daily for 3 rolofylline 10mg (n=74), 20mg (n=75) days. Administered with 40mg IV or 30mg (n=74); once daily for 3 days, furosemide 12 hrs before, and as necessary administered with IV loop diuretics. 6 hrs after, study drug. Follow-up Rehospitalisation and death rates at 60 30 days.

3 August 2008 National Horizon Scanning Centre News on emerging technologies in healthcare days. Primary Success - improvement in patient- Total urine output during first 6 hours. outcome reported dyspnoea at 24 and 48 hours. Failure - death, hospital re-admission, physician determined worsening heart failure or persistent renal impairment. Secondary Preferred dosage regimen; Urine flow rate, serum creatinine (SCr) at outcomes Safety. day 4, renal function at day 4 and treatment failure. Key results At 24 hours dyspnoea improved by 51% Rolofylline resulted in higher cumulative in the placebo group, and in the urine output during the first 6 hrs at all rolofylline groups by 62% (10mg), 63% doses compared to placebo - statistically (20mg) and 66% (30mg). Failure rates significant for the 30mg group (631±506ml were 33%, 32%, 24% and 19% vs. 374±190ml, p=0.02). By 24-hrs total respectively, providing a trend in the urine output similar for all groups. SCr had placebo vs. rolofylline hazard ratio of decreased with rolofylline relative to 0.55 (95% CI 0.28,1.04). baseline (-0.08, -0.03, -0.06 and -0.03 mg/dl), compared to a mean increase of +0.04 mg/dl for placebo (p=0.04 for 30mg vs. placebo) Adverse Rates of adverse events similar across Adverse effects (AE) occurred in 85% of effects treatment groups. No seizures occurred. placebo and 73-87% of rolofylline groups. Serious adverse events in 54 subjects (37%). Cardiac disorders were the most common AE reported.

Trial code, PROTECT-114: PROTECT -215: REACH UP16: pilot name, phase NCT00328692; NCT00354458; NCT00443690; rolofylline vs. placebo; rolofylline vs. placebo; rolofylline vs. placebo; phase III. phase III. phase III. Sponsor Merck & Co., Inc. Merck & Co., Inc. Merck & Co., Inc. Status Ongoing Ongoing Ongoing Location USA, Canada, Europe, USA, Europe (inc UK), USA, Europe (inc UK). Israel. Israel. Design Randomised, double-blind, Randomised, double-blind, Randomised, double- placebo-controlled. placebo-controlled. blind, placebo-controlled. Participants n=1000 (planned); adults; n=1000 (planned); adults; n=60; adults; dyspnoea at in trial hospitalised for AHF, hospitalised for AHF, rest or with minimal requiring IV diuretic requiring IV diuretic exertion, fluid overload, therapy, impaired renal therapy, impaired renal estimated CrCl 20- function. function. 60mL/min, worsening Randomised to placebo or Randomised to placebo or renal function, anticipated rolofylline both in addition rolofylline both in addition need for IV diuretic for at to IV loop diuretics. to IV loop diuretics. least 48hrs. Randomised to placebo or rolofylline 30 mg IV daily for 3 days, both in addition to IV loop diuretics. Follow-up 3, 60 and 180 –days. 3, 60 and 180 –days. 7-days. Primary Heart failure signs and Heart failure signs and Heart failure signs and outcome symptoms; renal function. symptoms; renal function. symptoms; renal function. Secondary Morbidity/mortality, renal Morbidity/mortality. Renal - outcomes outcomes outcomes

4 August 2008 National Horizon Scanning Centre News on emerging technologies in healthcare Expected December 2008 December 2008 July 2008 (completion reporting (completion date). (completion date). date). date Reporting Q3 2009. Reporting Q3 2009.

Estimated cost and cost impact The cost of rolofylline has not been determined. Rolofylline is intended to be used in addition to existing treatments (IV loop diuretics).

Potential or intended impact – speculative

Patients ; Reduced morbidity ; Reduced mortality or increased ; Improved quality of life for survival patients and/or carers Quicker, earlier or more accurate Other: None identified diagnosis or identification of disease

Services Increased use Service reorganisation required Staff or training required

; Decreased use: if hospital Other: None identified admission or length of stay is reduced.

Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed ; New costs: used in addition to IV ; Savings: if hospital admission or Other: loop diuretics length of stay is reduced

References

1 Smith GL, Lichtman JH, Bracken MB, et al. Renal impairment and outcomes in heart failure: systematic review and meta-analysis. Journal of the American College of Cardiology. 2006;47:1987-96. 2 Forman DE, Butler J, Wang Y, et al. Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure, Journal of the American College of Cardiology. 2004; 43:61-7. 3 National Institute for Health and Clinical Excellence. Neseritide for the treatment of heart failure. Technology appraisal in development. 4 National Institute for Health and Clinical Excellence. Cardiac resynchronisation therapy for the treatment of heart failure. Technology appraisal TA120. May 2007. 5 National Institute for Health and Clinical Excellence. Management of chronic heart failure in adults in primary and secondary care. Clinical guideline CG5. July 2003. 6 Scottish Intercollegiate Guideline Network. Management of Chronic Heart Failure: A national clinical guideline, No. 95, February 2007. 7 The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology, ESC Guidelines on the diagnosis and treatment of acute and chronic heart failure. European Heart Journal 2008: 29 doi:10.1093/eurheartj/ehn309. 8 The Information Centre for Health and Social care - Prescribing Support Unit, QMAS database – 2006/7 as at end of June 2007. 9 Hobbs FDR, Kenkre JE, Roalfe AK et al. Impact of heart failure and left ventricular systolic dysfunction on quality of life: a cross-sectional study comparing chronic cardiac and medical disorders and a representative adult population. European Journal of Heart Failure 2002;23:1867-1876. 10 Office for National Statistics. Mortality statistics: Deaths registered in 2006, DR_06, Newport: Office for National Statistics, 2008.

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11 The NHS Information Centre. Hospital Episode Statistics: Primary diagnosis 2005-2006, Available at: http://www.hesonline.org.uk/Ease/servlet/ContentServer?siteID=1937&categoryID=214 (Accessed 08/08/2008). 12 Cotter G, Dittrich HC, Davison Weatherley B 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. Journal of Cardiac Failure. 2008;14(8): 631-640. 13 Givertz MM, Massie BM, Fields TK et al. The effect of KW-3902, an adenosine A1 receptor antagonist, on diuresis and renal function in patients with acute decompensated heart failure and renal impairment or diuretic resistance. Journal of the American College of Cardiology, 2007;50(16):1551-60. 14 Clinical Trials. PROTECT-1: A study of the selective A1 adenosine receptor antagonist KW-3902 for patients hospitalised with acute heart failure and volume overload to assess treatment effect on congestion and renal function. Available at: http://clinicaltrials.gov/show/NCT00328692 (Accessed 08/08/2008). 15 Clinical Trials. PROTECT-2: A study of the selective A1 adenosine receptor antagonist KW-3902 for patients hospitalised with acute heart failure and volume overload to assess treatment effect on congestion and renal function. Available at: http://clinicaltrials.gov/show/NCT00354458 (Accessed 08/08/2008). 16 Clinical Trials. Placebo-controlled randomized study of KW-3902 for subjects hospitalised with worsening renal function and heart failure requiring IV therapy (REACH UP). Available at: http://clinicaltrials.gov/show/NCT00443690 (Accessed 08/08/2008).

The National Institute for Health Research National Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health

The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269 www.pcpoh.bham.ac.uk/publichealth/horizon

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