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Hypertension in the Very Elderly Trial (HYVET)

Protocol for the Main Trial

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Abstract

A number of trials and meta-analyses have demonstrated clear benefits of blood pressure (BP) reduction in patients aged <80 years with regard to the reduction in stroke and cardiovascular events. However, a variety of studies have suggested that the positive relationship between BP and cardiovascular mortality is weakened or indeed reversed in the very elderly. Most intervention trials to date have either excluded or not recruited sufficient patients aged ≥80 years to determine whether there is a significant benefit from treatment in this age group. A meta-analysis of intervention trials that recruited patients aged ≥80 years has suggested a benefit in terms of stroke reduction but has also raised the possibility of an increase in total mortality. The benefit to risk ratio therefore needs to be clearly established before recommendations can be made for treating very elderly patients with hypertension.

The Hypertension in the Very Elderly Trial (HYVET) pilot recruited 1283 patients aged ≥80 years and showed the feasibility of performing such a trial in this age group. It was a Prospective Randomised Open Blinded End-Points (PROBE) design but the main trial has additional pharmaceutical sponsorship to run a double-blind trial. Therefore, the main trial is a randomised, double-blind, placebo-controlled trial designed to assess the benefits of treating very elderly patients with hypertension. It compares placebo with a low dose diuretic (indapamide sustained release 1.5mg daily) and additional ACE inhibitor (perindopril) therapy if required.

As in the pilot trial, the primary end-point is stroke events (fatal and non-fatal) and the trial is designed to determine whether or not a 35% difference occurs between placebo and active treatment. The main objective will be achieved with 90% power at the 1% level of significance. Secondary outcome measures will include total mortality, cardiovascular mortality, cardiac mortality, stroke mortality and skeletal fracture.

2100 patients aged ≥80 years are to be recruited and followed up for an average of 5 years. Entry BP criteria after 2 months of a single-blind placebo run-in period are a sustained sitting systolic BP (SBP) of 160 to 199mm Hg and a diastolic BP of 90 to 109mm Hg. The standing SBP must be >140mm Hg. The trial will be carried out in accordance with the principles of Good Clinical Practice. We describe in detail the protocol for the main trial and discuss the reasons for the changes from the pilot, the use of the drug regimen, and the BP criteria to be used in the trial.

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Acknowledgements

As with the pilot trial the main HYVET trial is funded by the charity, the British Heart Foundation. However, there is additional support from the Institut de Recherches Internationales Servier. The Imperial College, London, has arranged the insurance for the trial. The following investigators took part in the pilot trial:

England and Scotland: S. Bailey (Chaderton), H. Bethel (Alton), N. Coni (Cambridge), J. Coope (Macclesfield), N. Gainsborough (Brighton), G. Greveson (Newcastle), P. McCaffrey (Lurgan), P. Murdoch (Falkirk), Pandita-Gunawardena (London), J. Potter (Leicester), C. Rajkumar (London), S. Soloman, (Oldham), B. Williams (Glasgow).

Bulgaria: S. Beleva (Vidin), R. Kermova (Pleven), S. Mantov (Stara Zagora), E. Mantova (Sophia), C. Nachev (Sophia), D. Popov (Sophia), V. Sirakova (Varna), D. Smilkova (Sophia), P. Solakov (Plovdiv), V. Stoyanovsky (Sophia), T. Vasileva (Dobrich), D. Yankulova (Bankya).

Finland: R. Antikainen (Oulu).

Romania: S. Babeanu (Bucharest), D. Dumitrascu (Cluj).

Spain: B. Gil-Extremera (Granada).

Lithuania: J. Arlauskas (Trakuraj).

Ireland: J. Duggan (Dublin).

Poland: Z. Chodorouski (Gdansk), T. Grodzicki (Krakow).

Greece: A. Efstratopoulos (Athens).

Serbia: M. Davidovic (Belgrade).

The Committees and national coordinators of the main HYVET trial are:

Steering Committee: J. Coope, B. Gil-Extremera, F. Forette, C. Nachev, J. Potter, P. Sever, J. Staessen, C. Swift, J. Tuomilehto.

Monitoring and Statistical Committee: J. Staessen, (chairman), A. Fletcher, L. Thijs, J. Cooke.

End-Point Committee: C. Davidson, (Chairman), J. Duggan, N. Gainsborough, MC. de Vernejoul.

Ethics Committee: R. Fagard (Chairman), L Ramsay, J Grimley Evans.

National Coordinators: R. Warne/I. Puddey (Australia), H. Celis (Belgium), C. Nachev (Bulgaria), L. Lisheng (China), R Antikainen (Finland), F. Forette (France), J. Duggan (Ireland), G. Gensini (Italy), T. Grodzicki (Poland), G. Clara (Portugal), D.L. Dumitrascu (Romania), L.B. Lazebnik (Russia), B. Gil-Extremera (Spain), B. Williams (UK).

Lead Investigator: C. Bulpitt

Co-investigator: A. Fletcher

Trial Coordinator: N. Beckett

Coordinating Staff: M. Nunes (epidemiologist), J. Cooke (statistician), R. Peters, J. Astarci, J. Grove.

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Authors and Affiliations

  1. Imperial College School of Medicine, Section of Elderly Care, Hammersmith Hospital, Du Cane Road, London, W12 0NN, England

    Christopher Bulpitt &  Nigel Beckett

  2. Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, England

    Astrid Fletcher

  3. The Waterhouse, Bollington, Nr. Macclesfield, England

    John Coope

  4. Departmento de Medicina, Universidad de Granada, Avenida de Madrid, Granada, Spain

    Blas Gil-Extremera

  5. Center of Gerontology, Pascal, National Foundation of Gerontology, Hopital Broca, Paris, France

    Françoise Forette

  6. Department of Internal Medicine, Alexandrov’s University Hospital, Sophia, Bulgaria

    Choudomir Nachev

  7. Department of Medicine for the Elderly, Glenfield General Hospital, Leicester, England

    John Potter

  8. Department of Clinical Pharmacology, NHLI St. Mary’s Campus, Paddington, London, England

    Peter Sever

  9. Study Coordinating Centre, Hypertension and Cardiovascular Rehabilitation Unit, Department of Molecular and Cardiovascular Research, Catholic University of Leuven, Leuven, Belgium

    Jan Staessen

  10. Department of Healthcare for the Elderly, King’s College School of Medicine and Dentistry, King’s College Hospital, Dulwich, London, England

    Cameron Swift

  11. Department of Public Health, University of Helskinki and Diabetes and Genetic Epidemiology Unit, National Public Health Institute, Mannerheimintie, Helsinki, Finland

    Jaakko Tuomilehto

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  1. Christopher Bulpitt
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  2. Astrid Fletcher
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  3. Nigel Beckett
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  4. John Coope
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  5. Blas Gil-Extremera
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  6. Françoise Forette
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  7. Choudomir Nachev
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  8. John Potter
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  9. Peter Sever
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  10. Jan Staessen
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  11. Cameron Swift
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  12. Jaakko Tuomilehto
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Correspondence to Nigel Beckett.

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Bulpitt, C., Fletcher, A., Beckett, N. et al. Hypertension in the Very Elderly Trial (HYVET). Drugs & Aging 18, 151–164 (2001). https://doi.org/10.2165/00002512-200118030-00001

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