Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial

Isla S. Mackenzie; Christopher J. Hawkey; Ian Ford; Nicola Greenlaw; Filippo Pigazzani; Amy Rogers; Allan D. Struthers; Alan G. Begg; Li Wei; Anthony J. Avery; Jaspal S. Taggar; Andrew Walker; Suzanne L. Duce; Rebecca J. Barr; Jennifer S. Dumbleton; Evelien D. Rooke; Jonathan N. Townend; Lewis D. Ritchie; Thomas M. MacDonald; Husnat Ahmed; Peter Arthur; Jane Aziz; Lawrence Barnes; Sarah Boyle; Tom Brighton; Morris Brown; Mark Caulfield; Jesse Dawson; Martin Denvir; Alexander SF Doney; Sagar Doshi; Moira Dryburgh; Michael Eddleston; Jim Finlayson; Ahmet Fuat; Jacqueline Furnace; JW Kerr Grieve; Greg Guthrie; Sharon Ham; Emma Isaard; Claudine Jennings; Richard Johnson; Claire Kerr; Sohail Khan; Kailash Krishnan; Susan Long; Anne Mackintosh; Mary Joan Macleod; Terry McCormack; Christopher Weir; ALL-HEART Study Group

doi:10.1016/S0140-6736(22)01657-9

Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial

Isla S. Mackenzie^*, Christopher J. Hawkey, Ian Ford, Nicola Greenlaw, Filippo Pigazzani, Amy Rogers, Allan D. Struthers, Alan G. Begg, Li Wei, Anthony J. Avery, Jaspal S. Taggar, Andrew Walker, Suzanne L. Duce, Rebecca J. Barr, Jennifer S. Dumbleton, Evelien D. Rooke, Jonathan N. Townend, Lewis D. Ritchie, Thomas M. MacDonald, Husnat AhmedPeter Arthur, Jane Aziz, Lawrence Barnes, Sarah Boyle, Tom Brighton, Morris Brown, Mark Caulfield, Jesse Dawson, Martin Denvir, Alexander SF Doney, Sagar Doshi, Moira Dryburgh, Michael Eddleston, Jim Finlayson, Ahmet Fuat, Jacqueline Furnace, JW Kerr Grieve, Greg Guthrie, Sharon Ham, Emma Isaard, Claudine Jennings, Richard Johnson, Claire Kerr, Sohail Khan, Kailash Krishnan, Susan Long, Anne Mackintosh, Mary Joan Macleod, Terry McCormack, Christopher Weir, ALL-HEART Study Group

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

62 Citations (Scopus)

1 Downloads (Pure)

Abstract

Background: Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease. Methods: ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426. Findings: Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89–1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87–1·20], p=0·77). Interpretation: In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care. Funding: UK National Institute for Health and Care Research.

Original language	English
Pages (from-to)	1195-1205
Number of pages	11
Journal	The Lancet
Volume	400
Issue number	10359
Early online date	7 Oct 2022
DOIs	https://doi.org/10.1016/S0140-6736(22)01657-9
Publication status	Published - 8 Oct 2022

Bibliographical note

Funding Information:
ISM reports research grants from Menarini, EMA, Sanofi, Health Data Research UK, the British Heart Foundation, and Innovative Medicines Initiative; institutional consultancy income from AstraZeneca outside the submitted work; and personal income from AstraZeneca and Amgen outside the submitted work. TMM reports grants from Menarini/Ipsen/Teijin and Merck Sharp & Dohme outside the submitted work, and personal income for consultancy from Novartis and AstraZeneca outside the submitted work, and is a trustee of the Scottish Heart Arterial Risk Prevention Society. AGB reports personal income from Novartis, Mylan, AstraZeneca, Bayer, Daiichi-Sankyo, Boehringer, Pfizer, Galderma, Zambon, and Novo-Nordisk outside the submitted work. ADS and the University of Dundee hold a European patent for the use of xanthine oxidase inhibitors in treating chest pain in angina pectoris. AW declares personal income for consultancy from AbbVie, Akcea, Albireo, Alexion, Allergan, Amarin, Apsara, Arena, Astellas, AstraZeneca, Autolus, Bayer, Biocryst, Biogen, Biomarin, Bristol Myers Squibb, Boehringer Ingelheim, Calico, Celgene, Chiesi, Daiichi Sankyo, Diurnal, Elsai, Eli Lilly, Ferring, Galapagos, Gedeon Richter, Gilead, GlaxoSmithKline, GW Pharma, Idorsia, Incyte, Intercept, Ionis, Ipsen, Janssen, Jazz, Jcyte, Kite Gilead, LEK, Leo Pharma, Les Laboratoires Servier, Lundbeck, Merck (Merck Sharp & Dohme), Merck-Serono, Mitenyi, Mundibiopharma, Mustang Bio, Mylan, Myovant, Norgine, Novartis, Novo Nordisk, Orchard, Paion, Pfizer, Pierre Fabre, PTC, RegenXBio, Rhythm, Sanofi, Santen, Sarepta, SeaGen, Shionogi, Sigmatec, SOBI, Takeda, Tanaya, UCB, and Vertex outside the submitted work. JST declares research funding from the UK National Institute for Health and Care Research (NIHR) and NHS England outside the submitted work and membership of a UK National Institute for Health and Care Excellence guideline committee on management of atrial fibrillation. All other authors declare no competing interests.

Funding Information:
This study was funded by the NIHR Health Technology Assessment programme (HTA 11/36/41 to ISM, IF, CJH, LW, ADS, AGB, AJA, AW, JST, and TMM). The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care. The study was supported by the Scottish Primary Care Research Network, Support for Science Scotland (Grampian, Highlands, Tayside, Fife, Forth Valley, Greater Glasgow and Clyde, Lothian, Ayrshire and Arran, Dumfries and Galloway, and Lanarkshire), and the NIHR Local Clinical Research Networks (East Midlands, West Midlands, Eastern, North Thames, Yorkshire and Humber, North East and North Cumbria, North West Coast, Kent, Surrey and Sussex, and South West Peninsula), which assisted with recruitment and other study activities. We thank Public Health Scotland and NHS Digital for providing data linkage. We thank all the participants, physicians, nurses, and other staff who participated in the ALL-HEART study.

Funding Information:
This study was funded by the NIHR Health Technology Assessment programme (HTA 11/36/41 to ISM, IF, CJH, LW, ADS, AGB, AJA, AW, JST, and TMM). The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care. The study was supported by the Scottish Primary Care Research Network, Support for Science Scotland (Grampian, Highlands, Tayside, Fife, Forth Valley, Greater Glasgow and Clyde, Lothian, Ayrshire and Arran, Dumfries and Galloway, and Lanarkshire), and the NIHR Local Clinical Research Networks (East Midlands, West Midlands, Eastern, North Thames, Yorkshire and Humber, North East and North Cumbria, North West Coast, Kent, Surrey and Sussex, and South West Peninsula), which assisted with recruitment and other study activities. We thank Public Health Scotland and NHS Digital for providing data linkage. We thank all the participants, physicians, nurses, and other staff who participated in the ALL-HEART study.

Publisher Copyright:
© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

Data Availability Statement

The datasets generated or analysed during the current study are not expected to be made available owing to the limitations of participant consent and approvals in place regarding data sharing between organisations involved in the study. The data will be held in the University of Dundee. Any applications for potential data sharing or collaboration should be made to the corresponding author and will be considered.

Access to Document

10.1016/S0140-6736(22)01657-9Licence: CC BY

Mackenzie-etal_lancet_Allopurinol_v_usual_VOR
https://creativecommons.org/licenses/by/4.0/
Final published version, 746 KBLicence: CC BY

Cite this

Mackenzie, I. S., Hawkey, C. J., Ford, I., Greenlaw, N., Pigazzani, F., Rogers, A., Struthers, A. D., Begg, A. G., Wei, L., Avery, A. J., Taggar, J. S., Walker, A., Duce, S. L., Barr, R. J., Dumbleton, J. S., Rooke, E. D., Townend, J. N., Ritchie, L. D., MacDonald, T. M., ... ALL-HEART Study Group (2022). Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial. The Lancet, 400(10359), 1195-1205. https://doi.org/10.1016/S0140-6736(22)01657-9

Mackenzie, IS, Hawkey, CJ, Ford, I, Greenlaw, N, Pigazzani, F, Rogers, A, Struthers, AD, Begg, AG, Wei, L, Avery, AJ, Taggar, JS, Walker, A, Duce, SL, Barr, RJ, Dumbleton, JS, Rooke, ED, Townend, JN, Ritchie, LD, MacDonald, TM, Ahmed, H, Arthur, P, Aziz, J, Barnes, L, Boyle, S, Brighton, T, Brown, M, Caulfield, M, Dawson, J, Denvir, M, Doney, ASF, Doshi, S, Dryburgh, M, Eddleston, M, Finlayson, J, Fuat, A, Furnace, J, Grieve, JWK, Guthrie, G, Ham, S, Isaard, E, Jennings, C, Johnson, R, Kerr, C, Khan, S, Krishnan, K, Long, S, Mackintosh, A, Macleod, MJ, McCormack, T, Weir, C & ALL-HEART Study Group 2022, 'Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial', The Lancet, vol. 400, no. 10359, pp. 1195-1205. https://doi.org/10.1016/S0140-6736(22)01657-9

@article{e68e1b737af64c9c9e2ea17a7112c78a,

title = "Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial",

abstract = "Background: Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease. Methods: ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426. Findings: Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89–1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87–1·20], p=0·77). Interpretation: In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care. Funding: UK National Institute for Health and Care Research.",

author = "Mackenzie, {Isla S.} and Hawkey, {Christopher J.} and Ian Ford and Nicola Greenlaw and Filippo Pigazzani and Amy Rogers and Struthers, {Allan D.} and Begg, {Alan G.} and Li Wei and Avery, {Anthony J.} and Taggar, {Jaspal S.} and Andrew Walker and Duce, {Suzanne L.} and Barr, {Rebecca J.} and Dumbleton, {Jennifer S.} and Rooke, {Evelien D.} and Townend, {Jonathan N.} and Ritchie, {Lewis D.} and MacDonald, {Thomas M.} and Husnat Ahmed and Peter Arthur and Jane Aziz and Lawrence Barnes and Sarah Boyle and Tom Brighton and Morris Brown and Mark Caulfield and Jesse Dawson and Martin Denvir and Doney, {Alexander SF} and Sagar Doshi and Moira Dryburgh and Michael Eddleston and Jim Finlayson and Ahmet Fuat and Jacqueline Furnace and Grieve, {JW Kerr} and Greg Guthrie and Sharon Ham and Emma Isaard and Claudine Jennings and Richard Johnson and Claire Kerr and Sohail Khan and Kailash Krishnan and Susan Long and Anne Mackintosh and Macleod, {Mary Joan} and Terry McCormack and Christopher Weir and {ALL-HEART Study Group}",

note = "Funding Information: ISM reports research grants from Menarini, EMA, Sanofi, Health Data Research UK, the British Heart Foundation, and Innovative Medicines Initiative; institutional consultancy income from AstraZeneca outside the submitted work; and personal income from AstraZeneca and Amgen outside the submitted work. TMM reports grants from Menarini/Ipsen/Teijin and Merck Sharp & Dohme outside the submitted work, and personal income for consultancy from Novartis and AstraZeneca outside the submitted work, and is a trustee of the Scottish Heart Arterial Risk Prevention Society. AGB reports personal income from Novartis, Mylan, AstraZeneca, Bayer, Daiichi-Sankyo, Boehringer, Pfizer, Galderma, Zambon, and Novo-Nordisk outside the submitted work. ADS and the University of Dundee hold a European patent for the use of xanthine oxidase inhibitors in treating chest pain in angina pectoris. AW declares personal income for consultancy from AbbVie, Akcea, Albireo, Alexion, Allergan, Amarin, Apsara, Arena, Astellas, AstraZeneca, Autolus, Bayer, Biocryst, Biogen, Biomarin, Bristol Myers Squibb, Boehringer Ingelheim, Calico, Celgene, Chiesi, Daiichi Sankyo, Diurnal, Elsai, Eli Lilly, Ferring, Galapagos, Gedeon Richter, Gilead, GlaxoSmithKline, GW Pharma, Idorsia, Incyte, Intercept, Ionis, Ipsen, Janssen, Jazz, Jcyte, Kite Gilead, LEK, Leo Pharma, Les Laboratoires Servier, Lundbeck, Merck (Merck Sharp & Dohme), Merck-Serono, Mitenyi, Mundibiopharma, Mustang Bio, Mylan, Myovant, Norgine, Novartis, Novo Nordisk, Orchard, Paion, Pfizer, Pierre Fabre, PTC, RegenXBio, Rhythm, Sanofi, Santen, Sarepta, SeaGen, Shionogi, Sigmatec, SOBI, Takeda, Tanaya, UCB, and Vertex outside the submitted work. JST declares research funding from the UK National Institute for Health and Care Research (NIHR) and NHS England outside the submitted work and membership of a UK National Institute for Health and Care Excellence guideline committee on management of atrial fibrillation. All other authors declare no competing interests. Funding Information: This study was funded by the NIHR Health Technology Assessment programme (HTA 11/36/41 to ISM, IF, CJH, LW, ADS, AGB, AJA, AW, JST, and TMM). The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care. The study was supported by the Scottish Primary Care Research Network, Support for Science Scotland (Grampian, Highlands, Tayside, Fife, Forth Valley, Greater Glasgow and Clyde, Lothian, Ayrshire and Arran, Dumfries and Galloway, and Lanarkshire), and the NIHR Local Clinical Research Networks (East Midlands, West Midlands, Eastern, North Thames, Yorkshire and Humber, North East and North Cumbria, North West Coast, Kent, Surrey and Sussex, and South West Peninsula), which assisted with recruitment and other study activities. We thank Public Health Scotland and NHS Digital for providing data linkage. We thank all the participants, physicians, nurses, and other staff who participated in the ALL-HEART study. Funding Information: This study was funded by the NIHR Health Technology Assessment programme (HTA 11/36/41 to ISM, IF, CJH, LW, ADS, AGB, AJA, AW, JST, and TMM). The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care. The study was supported by the Scottish Primary Care Research Network, Support for Science Scotland (Grampian, Highlands, Tayside, Fife, Forth Valley, Greater Glasgow and Clyde, Lothian, Ayrshire and Arran, Dumfries and Galloway, and Lanarkshire), and the NIHR Local Clinical Research Networks (East Midlands, West Midlands, Eastern, North Thames, Yorkshire and Humber, North East and North Cumbria, North West Coast, Kent, Surrey and Sussex, and South West Peninsula), which assisted with recruitment and other study activities. We thank Public Health Scotland and NHS Digital for providing data linkage. We thank all the participants, physicians, nurses, and other staff who participated in the ALL-HEART study. Publisher Copyright: {\textcopyright} 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license",

year = "2022",

month = oct,

day = "8",

doi = "10.1016/S0140-6736(22)01657-9",

language = "English",

volume = "400",

pages = "1195--1205",

journal = "The Lancet",

issn = "0140-6736",

publisher = "ACADEMIC PRESS INC ELSEVIER SCIENCE",

number = "10359",

}

TY - JOUR

T1 - Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART)

T2 - a multicentre, prospective, randomised, open-label, blinded-endpoint trial

AU - Mackenzie, Isla S.

AU - Hawkey, Christopher J.

AU - Ford, Ian

AU - Greenlaw, Nicola

AU - Pigazzani, Filippo

AU - Rogers, Amy

AU - Struthers, Allan D.

AU - Begg, Alan G.

AU - Wei, Li

AU - Avery, Anthony J.

AU - Taggar, Jaspal S.

AU - Walker, Andrew

AU - Duce, Suzanne L.

AU - Barr, Rebecca J.

AU - Dumbleton, Jennifer S.

AU - Rooke, Evelien D.

AU - Townend, Jonathan N.

AU - Ritchie, Lewis D.

AU - MacDonald, Thomas M.

AU - Ahmed, Husnat

AU - Arthur, Peter

AU - Aziz, Jane

AU - Barnes, Lawrence

AU - Boyle, Sarah

AU - Brighton, Tom

AU - Brown, Morris

AU - Caulfield, Mark

AU - Dawson, Jesse

AU - Denvir, Martin

AU - Doney, Alexander SF

AU - Doshi, Sagar

AU - Dryburgh, Moira

AU - Eddleston, Michael

AU - Finlayson, Jim

AU - Fuat, Ahmet

AU - Furnace, Jacqueline

AU - Grieve, JW Kerr

AU - Guthrie, Greg

AU - Ham, Sharon

AU - Isaard, Emma

AU - Jennings, Claudine

AU - Johnson, Richard

AU - Kerr, Claire

AU - Khan, Sohail

AU - Krishnan, Kailash

AU - Long, Susan

AU - Mackintosh, Anne

AU - Macleod, Mary Joan

AU - McCormack, Terry

AU - Weir, Christopher

AU - ALL-HEART Study Group

N1 - Funding Information: ISM reports research grants from Menarini, EMA, Sanofi, Health Data Research UK, the British Heart Foundation, and Innovative Medicines Initiative; institutional consultancy income from AstraZeneca outside the submitted work; and personal income from AstraZeneca and Amgen outside the submitted work. TMM reports grants from Menarini/Ipsen/Teijin and Merck Sharp & Dohme outside the submitted work, and personal income for consultancy from Novartis and AstraZeneca outside the submitted work, and is a trustee of the Scottish Heart Arterial Risk Prevention Society. AGB reports personal income from Novartis, Mylan, AstraZeneca, Bayer, Daiichi-Sankyo, Boehringer, Pfizer, Galderma, Zambon, and Novo-Nordisk outside the submitted work. ADS and the University of Dundee hold a European patent for the use of xanthine oxidase inhibitors in treating chest pain in angina pectoris. AW declares personal income for consultancy from AbbVie, Akcea, Albireo, Alexion, Allergan, Amarin, Apsara, Arena, Astellas, AstraZeneca, Autolus, Bayer, Biocryst, Biogen, Biomarin, Bristol Myers Squibb, Boehringer Ingelheim, Calico, Celgene, Chiesi, Daiichi Sankyo, Diurnal, Elsai, Eli Lilly, Ferring, Galapagos, Gedeon Richter, Gilead, GlaxoSmithKline, GW Pharma, Idorsia, Incyte, Intercept, Ionis, Ipsen, Janssen, Jazz, Jcyte, Kite Gilead, LEK, Leo Pharma, Les Laboratoires Servier, Lundbeck, Merck (Merck Sharp & Dohme), Merck-Serono, Mitenyi, Mundibiopharma, Mustang Bio, Mylan, Myovant, Norgine, Novartis, Novo Nordisk, Orchard, Paion, Pfizer, Pierre Fabre, PTC, RegenXBio, Rhythm, Sanofi, Santen, Sarepta, SeaGen, Shionogi, Sigmatec, SOBI, Takeda, Tanaya, UCB, and Vertex outside the submitted work. JST declares research funding from the UK National Institute for Health and Care Research (NIHR) and NHS England outside the submitted work and membership of a UK National Institute for Health and Care Excellence guideline committee on management of atrial fibrillation. All other authors declare no competing interests. Funding Information: This study was funded by the NIHR Health Technology Assessment programme (HTA 11/36/41 to ISM, IF, CJH, LW, ADS, AGB, AJA, AW, JST, and TMM). The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care. The study was supported by the Scottish Primary Care Research Network, Support for Science Scotland (Grampian, Highlands, Tayside, Fife, Forth Valley, Greater Glasgow and Clyde, Lothian, Ayrshire and Arran, Dumfries and Galloway, and Lanarkshire), and the NIHR Local Clinical Research Networks (East Midlands, West Midlands, Eastern, North Thames, Yorkshire and Humber, North East and North Cumbria, North West Coast, Kent, Surrey and Sussex, and South West Peninsula), which assisted with recruitment and other study activities. We thank Public Health Scotland and NHS Digital for providing data linkage. We thank all the participants, physicians, nurses, and other staff who participated in the ALL-HEART study. Funding Information: This study was funded by the NIHR Health Technology Assessment programme (HTA 11/36/41 to ISM, IF, CJH, LW, ADS, AGB, AJA, AW, JST, and TMM). The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care. The study was supported by the Scottish Primary Care Research Network, Support for Science Scotland (Grampian, Highlands, Tayside, Fife, Forth Valley, Greater Glasgow and Clyde, Lothian, Ayrshire and Arran, Dumfries and Galloway, and Lanarkshire), and the NIHR Local Clinical Research Networks (East Midlands, West Midlands, Eastern, North Thames, Yorkshire and Humber, North East and North Cumbria, North West Coast, Kent, Surrey and Sussex, and South West Peninsula), which assisted with recruitment and other study activities. We thank Public Health Scotland and NHS Digital for providing data linkage. We thank all the participants, physicians, nurses, and other staff who participated in the ALL-HEART study. Publisher Copyright: © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

PY - 2022/10/8

Y1 - 2022/10/8

N2 - Background: Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease. Methods: ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426. Findings: Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89–1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87–1·20], p=0·77). Interpretation: In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care. Funding: UK National Institute for Health and Care Research.

AB - Background: Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease. Methods: ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426. Findings: Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89–1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87–1·20], p=0·77). Interpretation: In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care. Funding: UK National Institute for Health and Care Research.

UR - http://www.scopus.com/inward/record.url?scp=85139342056&partnerID=8YFLogxK

U2 - 10.1016/S0140-6736(22)01657-9

DO - 10.1016/S0140-6736(22)01657-9

M3 - Article

C2 - 36216006

AN - SCOPUS:85139342056

SN - 0140-6736

VL - 400

SP - 1195

EP - 1205

JO - The Lancet

JF - The Lancet

IS - 10359

ER -

Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial

Abstract

Bibliographical note

Data Availability Statement

Access to Document

Other files and links

Fingerprint

Cite this