Is Spironolactone Safe and Effective in the Treatment of Cardiovascular Disease in Mild Chronic Renal Failure?

NCT00291720 | Completed Phase 2 DMC

• 2 other identifiers: RPK274904/Q2707/294
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

Patients with kidney failure have a poor survival rate that is due to a much higher than average rate of heart and vascular disease. The reason that kidney failure causes heart disease is unknown but recent research suggests that a hormone called aldosterone, which is increased in patients with kidney disease may damage the heart and blood vessels. The investigators propose, using a randomized blinded trial, to find out whether drugs that inhibit the actions of aldosterone have beneficial effects on the cardiovascular system in patients with kidney failure

Conditions

Chronic Kidney Disease; Cardiovascular Disease

Keywords

Aldosterone; Spironolactone; Chronic Kidney Disease; Arterial Stiffness

Outcome Measures

Primary Outcomes (1)

• Changes in left ventricular mass on cardiac MRI and arterial stiffness (assessed by pulse wave velocity).

  9 months

Secondary Outcomes (1)

• Changes in aortic distensibility and large vessel augmentation

  9 months

Study Arms (2)

Spironolactone

ACTIVE COMPARATOR

25mg spironolactone daily

Drug: Spironolactone

Placebo

PLACEBO COMPARATOR

matching placebo medication for the control group

Drug: Placebo

Interventions

Spironolactone DRUG

All patients receive a 4 week open labeled run in phase of 25mg spironolactone daily after which they are randomized to continue or receive matched placebo for 8 months.

Spironolactone

Placebo DRUG

matching placebo

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Mild-moderate chronic kidney disease (glomerular filtration rate \[GFR\] 40-80 mls/min calculated by Cockroft-Gault equation)
• Controlled blood pressure (\< 130/80 mmHg)
• On established (\> 6 weeks) treatment with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs).

You may not qualify if:

• Diabetes mellitus
• Clinical evidence of fluid overload or hypovolaemia
• Recent (\< 2 months) acute myocardial infarction
• Left ventricular (LV) dysfunction (ejection fraction \< 40% by echocardiography).

Sponsors & Collaborators

• University Hospital Birmingham: lead
• British Heart Foundation: collaborator

Study Sites (1)

University Hospital Birmingham

Birmingham, West Midlands, B15 2TH, United Kingdom

Location

Related Publications (21)

• Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis. 1998 Nov;32(5 Suppl 3):S112-9. doi: 10.1053/ajkd.1998.v32.pm9820470. No abstract available.

  PMID: 9820470 BACKGROUND

• Culleton BF, Larson MG, Wilson PW, Evans JC, Parfrey PS, Levy D. Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. Kidney Int. 1999 Dec;56(6):2214-9. doi: 10.1046/j.1523-1755.1999.00773.x.

  PMID: 10594797 BACKGROUND

• Coulden RA, Moss H, Graves MJ, Lomas DJ, Appleton DS, Weissberg PL. High resolution magnetic resonance imaging of atherosclerosis and the response to balloon angioplasty. Heart. 2000 Feb;83(2):188-91. doi: 10.1136/heart.83.2.188.

  PMID: 10648495 BACKGROUND

• Thambyrajah J, Landray MJ, McGlynn FJ, Jones HJ, Wheeler DC, Townend JN. Does folic acid decrease plasma homocysteine and improve endothelial function in patients with predialysis renal failure? Circulation. 2000 Aug 22;102(8):871-5. doi: 10.1161/01.cir.102.8.871.

  PMID: 10952955 BACKGROUND

• Landray MJ, Thambyrajah J, McGlynn FJ, Jones HJ, Baigent C, Kendall MJ, Townend JN, Wheeler DC. Epidemiological evaluation of known and suspected cardiovascular risk factors in chronic renal impairment. Am J Kidney Dis. 2001 Sep;38(3):537-46. doi: 10.1053/ajkd.2001.26850.

  PMID: 11532686 BACKGROUND

• Jardine AG, McLaughlin K. Cardiovascular complications of renal disease. Heart. 2001 Oct;86(4):459-66. doi: 10.1136/heart.86.4.459. No abstract available.

  PMID: 11559693 BACKGROUND

• Heart Outcomes Prevention Evaluation Study Investigators; Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000 Jan 20;342(3):145-53. doi: 10.1056/NEJM200001203420301.

  PMID: 10639539 BACKGROUND

• Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999 Sep 2;341(10):709-17. doi: 10.1056/NEJM199909023411001.

  PMID: 10471456 BACKGROUND

• Brown NJ. Eplerenone: cardiovascular protection. Circulation. 2003 May 20;107(19):2512-8. doi: 10.1161/01.CIR.0000071081.35693.9A.

  PMID: 12756192 BACKGROUND

• Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003 Apr 3;348(14):1309-21. doi: 10.1056/NEJMoa030207. Epub 2003 Mar 31.

  PMID: 12668699 BACKGROUND

• Rocha R, Stier CT Jr, Kifor I, Ochoa-Maya MR, Rennke HG, Williams GH, Adler GK. Aldosterone: a mediator of myocardial necrosis and renal arteriopathy. Endocrinology. 2000 Oct;141(10):3871-8. doi: 10.1210/endo.141.10.7711.

  PMID: 11014244 BACKGROUND

• Sato T, Nishinaga M, Kawamoto A, Ozawa T, Takatsuji H. Accuracy of a continuous blood pressure monitor based on arterial tonometry. Hypertension. 1993 Jun;21(6 Pt 1):866-74. doi: 10.1161/01.hyp.21.6.866.

  PMID: 8500866 BACKGROUND

• Epstein M. Aldosterone as a determinant of cardiovascular and renal dysfunction. J R Soc Med. 2001 Aug;94(8):378-83. doi: 10.1177/014107680109400803. No abstract available.

  PMID: 11461980 BACKGROUND

• Foley RN, Parfrey PS, Kent GM, Harnett JD, Murray DC, Barre PE. Serial change in echocardiographic parameters and cardiac failure in end-stage renal disease. J Am Soc Nephrol. 2000 May;11(5):912-916. doi: 10.1681/ASN.V115912.

  PMID: 10770969 BACKGROUND

• London GM, Guerin AP, Marchais SJ, Pannier B, Safar ME, Day M, Metivier F. Cardiac and arterial interactions in end-stage renal disease. Kidney Int. 1996 Aug;50(2):600-8. doi: 10.1038/ki.1996.355.

  PMID: 8840292 BACKGROUND

• Guerin AP, Blacher J, Pannier B, Marchais SJ, Safar ME, London GM. Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure. Circulation. 2001 Feb 20;103(7):987-92. doi: 10.1161/01.cir.103.7.987.

  PMID: 11181474 BACKGROUND

• Wilkinson IB, Fuchs SA, Jansen IM, Spratt JC, Murray GD, Cockcroft JR, Webb DJ. Reproducibility of pulse wave velocity and augmentation index measured by pulse wave analysis. J Hypertens. 1998 Dec;16(12 Pt 2):2079-84. doi: 10.1097/00004872-199816121-00033.

  PMID: 9886900 BACKGROUND

• Chung EY, Ruospo M, Natale P, Bolignano D, Navaneethan SD, Palmer SC, Strippoli GF. Aldosterone antagonists in addition to renin angiotensin system antagonists for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 2020 Oct 27;10(10):CD007004. doi: 10.1002/14651858.CD007004.pub4.

  PMID: 33107592 DERIVED

• Hammer F, Edwards NC, Hughes BA, Steeds RP, Ferro CJ, Townend JN, Stewart PM. The effect of spironolactone upon corticosteroid hormone metabolism in patients with early stage chronic kidney disease. Clin Endocrinol (Oxf). 2010 Nov;73(5):566-72. doi: 10.1111/j.1365-2265.2010.03832.x.

  PMID: 20550533 DERIVED

• Edwards NC, Steeds RP, Stewart PM, Ferro CJ, Townend JN. Effect of spironolactone on left ventricular mass and aortic stiffness in early-stage chronic kidney disease: a randomized controlled trial. J Am Coll Cardiol. 2009 Aug 4;54(6):505-12. doi: 10.1016/j.jacc.2009.03.066.

  PMID: 19643310 DERIVED

• Edwards NC, Ferro CJ, Townend JN, Steeds RP. Aortic distensibility and arterial-ventricular coupling in early chronic kidney disease: a pattern resembling heart failure with preserved ejection fraction. Heart. 2008 Aug;94(8):1038-43. doi: 10.1136/hrt.2007.137539. Epub 2008 Feb 28.

  PMID: 18308865 DERIVED

MeSH Terms

Conditions

Renal Insufficiency, Chronic; Cardiovascular Diseases

Interventions

Spironolactone

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• John N Townend, BSc, MB ChB, MD, FRCP, FESC

  University Hospital Birmingham

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: February 13, 2006
• First Posted: February 14, 2006
• Study Start: April 1, 2005
• Primary Completion: December 1, 2007
• Study Completion: December 1, 2007
• Last Updated: May 21, 2008

Record last verified: 2008-05

Locations

GB (1)