Heart FailureBB-META-HFNCT00832442
Collaborative Systematic Overview of Randomised Controlled Trials of Beta-Blockers in the Treatment of Heart Failure
An observational study of Heart Failure, run by Royal Brompton & Harefield NHS Foundation Trust at 2 sites in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Heart Failure
- What is being tested?
- Beta blocker
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 18,240 participants
- Where
- 2 sitesUnited Kingdom
- Study dates
- Aug 2008to Dec 2012
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Meta-Analysis of randomised controlled trials investigating mortality \& morbidity of placebo versus beta-blockers in heart failure
Who may be able to join
- 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)
Who cannot join
- Trial sample size of less than 300 patients
Trial locations and contacts
2 sites in 1 country.
United Kingdom2 sites
Clinical Trials & Evaluation Unit, Royal Brompton Hospital
London
Centre for Statistics in Medicine, University of Oxford
Oxford
About this study
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.
- Conditions
- Heart Failure
- Being tested
- Beta blocker, Placebo
- Keywords
- Beta blocker, Heart Failure, Meta analysis, Individual patient data
- Medical subject headings
- Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Beta blockerDrug
Also called Metoprolol, Bucindolol, Carvedilol, Bisoprolol
as determined by individual study
PlaceboOther
in addition to usual care
| Study group | Role | What they receive |
|---|---|---|
| Beta blocker | Not described Receives: Drug: Beta blocker | |
| Placebo | Not described Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Beta-blocker therapy improves overall mortality and morbidity in symptomatic heart failure in an individual patient meta-analysis
Measured: variable (time to event)
Secondary outcomes (6)
Beta-blocker therapy improves mortality and morbidity in both elderly patients and women
Measured: variable (time to event)
Beta-blocker therapy improves mortality and morbidity in patients with co-morbidities (diabetes, renal dysfunction, COPD, peripheral arterial disease or atrial fibrillation)
Measured: variable (time to event)
The benefit of beta-blockers is not modified by concomitant cardiovascular therapy
Measured: variable (time to event)
The benefit of beta-blockers is independent of left ventricular ejection fraction at baseline
Measured: variable (time to event)
The clinical benefit is dependent on the resting heart rate achieved whatever the dose achieved or agent used
Measured: variable (time to event)
Adverse side effects of beta blocker therapy do not significantly impact on clinical benefit (as a whole and in relevant sub-groups)
Measured: variable (time to event)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Jan 2009 (estimated)
- Study startAug 2008
- Primary completionDec 2012 (estimated)
- Study completionDec 2012 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (14)Papers the sponsor has linked to this study.
- Other trials for Heart FailureStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Enrolment
- 18,240 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Royal Brompton & Harefield NHS Foundation Trust
- Sponsor type
- University, hospital or other
- Collaborators
- University of Oxford
- Responsible party
- Sponsor
- Investigators
- Marcus Flather, Study chair, Royal Brompton Hospital, LondonLuis Manzano, Study chair, Universidad de Alcala, MadridDipak Kotecha, Study chair, Royal Brompton Hospital, LondonHenry Krum, Study chair, Monash University, Melbourne
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00832442
- Sponsor's protocol ID
- CTEU08/d5/BBHF
- Acronym
- BB-META-HF
- Status last verified
- Jan 2009
- First submitted
- 28 Jan 2009
- Last updated
- 9 May 2012
- Results posted
- No
- Data monitoring committee
- Yes
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. doi: 10.1016/0140-6736(93)92930-r.
PubMed 7902479A 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. doi: 10.1161/01.cir.90.4.1765.
PubMed 7923660Randomised, 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.
PubMed 9033462Packer 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. doi: 10.1056/NEJM199605233342101.
PubMed 8614419The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999 Jan 2;353(9146):9-13.
PubMed 10023943Packer 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. doi: 10.1056/NEJM200105313442201.
PubMed 11386263Beta-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. doi: 10.1056/NEJM200105313442202.
PubMed 11386264Flather 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, Bohm 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. doi: 10.1093/eurheartj/ehi115. Epub 2005 Jan 9.
PubMed 15642700Dargie 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. doi: 10.1016/s0140-6736(00)04560-8.
PubMed 11356434Banerjee A, Pasea L, Chung SC, Direk K, Asselbergs FW, Grobbee DE, Kotecha D, Anker SD, Dyszynski T, Tyl B, Denaxas S, Lumbers RT, Hemingway H. A population-based study of 92 clinically recognized risk factors for heart failure: co-occurrence, prognosis and preventive potential. Eur J Heart Fail. 2022 Mar;24(3):466-480. doi: 10.1002/ejhf.2417. Epub 2022 Jan 26.
PubMed 34969173Karwath A, Bunting KV, Gill SK, Tica O, Pendleton S, Aziz F, Barsky AD, Chernbumroong S, Duan J, Mobley AR, Cardoso VR, Slater K, Williams JA, Bruce EJ, Wang X, Flather MD, Coats AJS, Gkoutos GV, Kotecha D; card AIc group and the Beta-blockers in Heart Failure Collaborative Group. Redefining beta-blocker response in heart failure patients with sinus rhythm and atrial fibrillation: a machine learning cluster analysis. Lancet. 2021 Oct 16;398(10309):1427-1435. doi: 10.1016/S0140-6736(21)01638-X. Epub 2021 Aug 30.
PubMed 34474011Kotecha 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, Bohm M, Flather MD; Beta-Blockers in Heart Failure Collaborative Group. Effect of age and sex on efficacy and tolerability of beta 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.
PubMed 27098105Kotecha 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 beta 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.
PubMed 25193873Kotecha 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.
PubMed 23327629
Study at a glance
From the registry record, last updated by the sponsor on 9 May 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Collaborative Systematic Overview of Randomised Controlled Trials of Beta-Blockers in the Treatment of Heart Failure
- ClinicalTrials.gov ID
- NCT00832442
- Acronym / sponsor ID
- BB-META-HF / CTEU08/d5/BBHF
- Conditions
- Heart Failure
- Keywords
- Beta blocker, Heart Failure, Meta analysis, Individual patient data
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 18,240 participants (estimated)
- Lead sponsor
- Royal Brompton & Harefield NHS Foundation TrustUniversity, hospital or other
- Collaborators
- University of Oxford
- Study start
- Aug 2008
- Primary completion
- Dec 2012 (estimated)
- Study completion
- Dec 2012 (estimated)
- First posted
- 30 Jan 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Beta blocker | – | Drug: Beta blocker |
| Placebo | – | Other: Placebo |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Meta-Analysis of randomised controlled trials investigating mortality \& morbidity of placebo versus beta-blockers in heart failure
Key inclusion criteria (3 listed)
- 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)
Key exclusion criteria (1 listed)
- Trial sample size of less than 300 patients
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Beta blockerAlso: Metoprolol, Bucindolol, Carvedilol, Bisoprololas determined by individual study | Drug | Beta blocker |
| Placeboin addition to usual care | Other | Placebo |
Primary outcome
Beta-blocker therapy improves overall mortality and morbidity in symptomatic heart failure in an individual patient meta-analysis
Time frame: variable (time to event)
6 secondary outcomes
Beta-blocker therapy improves mortality and morbidity in both elderly patients and women
Time frame: variable (time to event)
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)
The benefit of beta-blockers is not modified by concomitant cardiovascular therapy
Time frame: variable (time to event)
The benefit of beta-blockers is independent of left ventricular ejection fraction at baseline
Time frame: variable (time to event)
The clinical benefit is dependent on the resting heart rate achieved whatever the dose achieved or agent used
Time frame: variable (time to event)
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)
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 May 2012.
- Background: PubMed 7902479Waagstein 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. doi: 10.1016/0140-6736(93)92930-r.
- Background: PubMed 7923660A 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. doi: 10.1161/01.cir.90.4.1765.
- Background: PubMed 9033462Randomised, 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.
- Background: PubMed 8614419Packer 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. doi: 10.1056/NEJM199605233342101.
- Background: PubMed 10023943The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999 Jan 2;353(9146):9-13.
- Background: PubMed 11386263Packer 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. doi: 10.1056/NEJM200105313442201.
- Background: PubMed 11386264Beta-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. doi: 10.1056/NEJM200105313442202.
- Background: PubMed 15642700Flather 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, Bohm 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. doi: 10.1093/eurheartj/ehi115. Epub 2005 Jan 9.
- Background: PubMed 11356434Dargie 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. doi: 10.1016/s0140-6736(00)04560-8.
- Derived from this study: PubMed 34969173Banerjee A, Pasea L, Chung SC, Direk K, Asselbergs FW, Grobbee DE, Kotecha D, Anker SD, Dyszynski T, Tyl B, Denaxas S, Lumbers RT, Hemingway H. A population-based study of 92 clinically recognized risk factors for heart failure: co-occurrence, prognosis and preventive potential. Eur J Heart Fail. 2022 Mar;24(3):466-480. doi: 10.1002/ejhf.2417. Epub 2022 Jan 26.
- Derived from this study: PubMed 34474011Karwath A, Bunting KV, Gill SK, Tica O, Pendleton S, Aziz F, Barsky AD, Chernbumroong S, Duan J, Mobley AR, Cardoso VR, Slater K, Williams JA, Bruce EJ, Wang X, Flather MD, Coats AJS, Gkoutos GV, Kotecha D; card AIc group and the Beta-blockers in Heart Failure Collaborative Group. Redefining beta-blocker response in heart failure patients with sinus rhythm and atrial fibrillation: a machine learning cluster analysis. Lancet. 2021 Oct 16;398(10309):1427-1435. doi: 10.1016/S0140-6736(21)01638-X. Epub 2021 Aug 30.
- Derived from this study: PubMed 27098105Kotecha 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, Bohm M, Flather MD; Beta-Blockers in Heart Failure Collaborative Group. Effect of age and sex on efficacy and tolerability of beta 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Marcus Flather study chair
Royal Brompton Hospital, London
Luis Manzano study chair
Universidad de Alcala, Madrid
Dipak Kotecha study chair
Royal Brompton Hospital, London
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Heart Failure, run by Royal Brompton & Harefield NHS Foundation Trust at 2 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 9 May 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Beta-blocker therapy improves overall mortality and morbidity in symptomatic heart failure in an individual patient meta-analysis (time frame: variable (time to event)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00832442, which also lists 14 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 May 2012.