Collaborative Systematic Overview of Randomised Controlled Trials of Beta-Blockers in the Treatment of Heart Failure (BB-META-HF)

Study Description

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

Several large trials have shown that beta-blocker treatment reduces the risk of death and hospital admission in patients with symptomatic heart failure. Unfortunately, survey data suggests relatively poor utilisation of beta-blockers, despite ample evidence for good tolerability. Additionally there are several important unanswered questions, such as clinical efficacy for specific sub-populations (women, the elderly and patients with diabetes or other co-morbidities) and the effect of beta-blockers in combination with other medications. Previous meta-analyses, based on published tabular data, have been conducted although this approach has important biases and limitations.

We plan to perform a carefully conducted systematic review of individual patient data from the major randomised trials of beta-blockers in heart failure. The goals of this collaborative project are to clarify the overall efficacy of beta-blockers and identify sub-groups that show particular benefit, thereby increasing the use of beta-blockers, reducing adverse clinical outcomes and the high costs associated with this condition.

Condition or disease	Intervention/treatment
Heart Failure	Drug: Beta blocker; Other: Placebo

Study Design

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Study Type :	Observational
Estimated Enrollment :	18240 participants
Official Title:	Collaborative Systematic Overview of Randomised Controlled Trials of Beta-Blockers in the Treatment of Heart Failure
Study Start Date :	August 2008
Estimated Primary Completion Date :	December 2012
Estimated Study Completion Date :	December 2012

Groups and Cohorts

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Group/Cohort	Intervention/treatment
Beta blocker	Drug: Beta blocker; as determined by individual study; Other Names: Metoprolol; Bucindolol; Carvedilol; Bisoprolol; Nebivolol
Placebo	Other: Placebo; in addition to usual care

Outcome Measures

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Primary Outcome Measures :

1. Beta-blocker therapy improves overall mortality and morbidity in symptomatic heart failure in an individual patient meta-analysis [ Time Frame: variable (time to event) ]

Secondary Outcome Measures :

1. Beta-blocker therapy improves mortality and morbidity in both elderly patients and women [ Time Frame: variable (time to event) ]
2. Beta-blocker therapy improves mortality and morbidity in patients with co-morbidities (diabetes, renal dysfunction, COPD, peripheral arterial disease or atrial fibrillation) [ Time Frame: variable (time to event) ]
3. The benefit of beta-blockers is not modified by concomitant cardiovascular therapy [ Time Frame: variable (time to event) ]
4. The benefit of beta-blockers is independent of left ventricular ejection fraction at baseline [ Time Frame: variable (time to event) ]
5. The clinical benefit is dependent on the resting heart rate achieved whatever the dose achieved or agent used [ Time Frame: variable (time to event) ]
6. Adverse side effects of beta blocker therapy do not significantly impact on clinical benefit (as a whole and in relevant sub-groups) [ Time Frame: variable (time to event) ]

Eligibility Criteria

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Ages Eligible for Study:	Child, Adult, Senior
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No
Sampling Method:	Non-Probability Sample

Study Population

Meta-Analysis of randomised controlled trials investigating mortality & morbidity of placebo versus beta-blockers in heart failure

Criteria

Inclusion Criteria:

• Randomised control trials of beta-blocker versus control in patients with documented heart failure
• Unconfounded trials only (in which one treatment group differed from another only by the beta-blocker therapy of interest)
• Randomization process precluded prior knowledge of the next treatment (for example trials in which treatment allocation was alternate or based on odd or even dates would not be included)

Exclusion Criteria:

• Trial sample size of less than 300 patients

Contacts and Locations

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United Kingdom
Clinical Trials & Evaluation Unit, Royal Brompton Hospital
London, United Kingdom
Centre for Statistics in Medicine, University of Oxford
Oxford, United Kingdom

Sponsors and Collaborators

Royal Brompton & Harefield NHS Foundation Trust

University of Oxford

Investigators

Study Chair:	Marcus Flather	Royal Brompton Hospital, London
Study Chair:	Luis Manzano	Universidad de Alcala, Madrid
Study Chair:	Dipak Kotecha	Royal Brompton Hospital, London
Study Chair:	Henry Krum	Monash University, Melbourne

More Information

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

Clinical Trials & Evaluation Unit 

Monash Centre of Cardiovascular Research & Education (CCRE) in Therapeutics 

Publications:

Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, Gilbert EM, Johnson MR, Goss FG, Hjalmarson A. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Lancet. 1993 Dec 11;342(8885):1441-6.

A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and Committees. Circulation. 1994 Oct;90(4):1765-73.

Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Australia/New Zealand Heart Failure Research Collaborative Group. Lancet. 1997 Feb 8;349(9049):375-80.

Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996 May 23;334(21):1349-55.

The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999 Jan 2;353(9146):9-13.

Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL; Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001 May 31;344(22):1651-8.

Beta-Blocker Evaluation of Survival Trial Investigators, Eichhorn EJ, Domanski MJ, Krause-Steinrauf H, Bristow MR, Lavori PW. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001 May 31;344(22):1659-67.

Flather MD, Shibata MC, Coats AJ, Van Veldhuisen DJ, Parkhomenko A, Borbola J, Cohen-Solal A, Dumitrascu D, Ferrari R, Lechat P, Soler-Soler J, Tavazzi L, Spinarova L, Toman J, Böhm M, Anker SD, Thompson SG, Poole-Wilson PA; SENIORS Investigators. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005 Feb;26(3):215-25. Epub 2005 Jan 9.

Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet. 2001 May 5;357(9266):1385-90.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kotecha D, Manzano L, Krum H, Rosano G, Holmes J, Altman DG, Collins PD, Packer M, Wikstrand J, Coats AJ, Cleland JG, Kirchhof P, von Lueder TG, Rigby AS, Andersson B, Lip GY, van Veldhuisen DJ, Shibata MC, Wedel H, Böhm M, Flather MD; Beta-Blockers in Heart Failure Collaborative Group. Effect of age and sex on efficacy and tolerability of β blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis. BMJ. 2016 Apr 20;353:i1855. doi: 10.1136/bmj.i1855. Review.

Kotecha D, Holmes J, Krum H, Altman DG, Manzano L, Cleland JG, Lip GY, Coats AJ, Andersson B, Kirchhof P, von Lueder TG, Wedel H, Rosano G, Shibata MC, Rigby A, Flather MD; Beta-Blockers in Heart Failure Collaborative Group. Efficacy of β blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet. 2014 Dec 20;384(9961):2235-43. doi: 10.1016/S0140-6736(14)61373-8. Epub 2014 Sep 2.

Kotecha D, Manzano L, Altman DG, Krum H, Erdem G, Williams N, Flather MD; Beta-Blockers in Heart Failure Collaborative Group. Individual patient data meta-analysis of beta-blockers in heart failure: rationale and design. Syst Rev. 2013 Jan 18;2:7. doi: 10.1186/2046-4053-2-7.

Responsible Party:	Royal Brompton & Harefield NHS Foundation Trust
ClinicalTrials.gov Identifier:	NCT00832442 History of Changes
Other Study ID Numbers:	CTEU08/d5/BBHF
First Posted:	January 30, 2009
Last Update Posted:	May 9, 2012
Last Verified:	January 2009

Keywords provided by Royal Brompton & Harefield NHS Foundation Trust:

Beta blocker; Heart Failure; Meta analysis; Individual patient data

Additional relevant MeSH terms:

Heart Failure; Heart Diseases; Cardiovascular Diseases; Adrenergic beta-Antagonists; Adrenergic Antagonists	Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs