The first morbidity/mortality
trial to answer the questions
of antihypertensive treatment
benefits in very elderly hypertensives
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HYVET: landmark trial voted 2008 Trial of the Year by the ImpACT/Society for Clinical Trials and the American Heart Association

Atlanta, Georgia US, 4 May, 2009 - HYVET (HYpertension in the Very Elderly Trial)1 has been unanimously voted as 2008 Trial of the Year by the prestigious Project ImpACT (Important Achievements of Clinical Trials) and the Society for Clinical Trials. HYVET was judged a landmark clinical trial, in terms of design, execution, and results. Evidence that effective antihypertensive treatment with indapamide sustained release 1.5 mg (Natrilix SR) in patients aged 80 or more prevents the fatal and debilitating consequences of hypertension such as stroke, heart failure, and dementia is likely to impact on guidelines and change the clinical management of very elderly patients with hypertension. This is especially relevant as this age group is the fastest growing globally, with growth rates expected to triple by 2050.2 Emeritus Professor Christopher Bulpitt, the lead investigator on the HYVET study from the Care of the Elderly Group at Imperial College London, UK, said: “I am very grateful to all who either worked on the trial or supported it in some way. The trial was entirely a collaborative effort. Our results clearly show that many patients aged 80 and over could benefit greatly from treatment.’

Increasing systolic blood pressure is part of the ‘normal’ aging process. Almost all very elderly patients (80 or over) have systolic hypertension (systolic blood pressure ≥160 mm Hg). Before HYVET, doctors were unsure whether these patients would obtain the same benefits from treatment to lower their blood pressure as those observed in younger people, as these very elderly patients had been largely excluded from previous clinical trials.

HYVET was the largest ever clinical trial to address this question. In total, 3845 patients were randomized to once daily treatment with placebo or the diuretic indapamide sustained release 1.5 mg (Natrilix SR), with the addition of the angiotensin-converting enzyme inhibitor perindopril 2-4 mg as necessary. Natrilix SR was used as it has proven efficacy in lowering blood pressure, particularly systolic blood pressure, in the long term.3 In July 2007 the trial was stopped early on the recommendation of an independent data monitoring committee after observation of significant reductions in overall mortality and stroke in those receiving treatment. Final results showed reductions of 21% (p=0.02) in total deaths, 39% (p=0.05) in stroke-related death, 64% (p<0.001) in fatal and nonfatal heart failure, and 34% (p<0.001) in cardiovascular events.1 There was also evidence from the HYVET-COG substudy that blood pressure lowering may reduce or delay dementia.4 According to Nigel S. Beckett, M.D., the trial coordinator from the Care of the Elderly group at Imperial College London: ‘The results of HYVET will have important implications for the generation of future guidelines and mean that very elderly individuals with sustained systolic blood pressures of 160 mm Hg or more should now be appropriately assessed and treated in accordance with these findings.’

HYVET has received other important awards which reinforce its landmark status. In January 2009, the American Heart Association voted HYVET as among the top 10 major advances in heart disease and stroke research for 2008.5 According to Timothy Gardner, M.D., President of the American Heart Association: ‘The results of HYVET demonstrate that effective antihypertensive treatment with indapamide (Natrilix SR) in persons aged 80 years old or older, is beneficial in reducing the risk of cardiovascular events, and thus extends the patient group in whom prevention must be pursued.’

HYVET was also nominated as the most important clinical trial of the year by Medscape, an online resource for clinicians.6 Commenting on the trial on Medscape Cardiology, Professor Henry R. Black, M.D., Clinical Professor of Internal Medicine, New York University School of Medicine, Center for Prevention of Cardiovascular Disease, USA, and President of the American Society of Hypertension, said ‘HYVET has filled in the gap in clinical management of hypertension in the very elderly.’

Furthermore, HYVET was identified as exceptional among the All time Top 10 list for clinical trials compiled by Faculty of 1000 Medicine,7 an online resource provided by expert researchers and clinicians. Deepak Bhatt, M.D., Chief of Cardiology, Veterans Affairs Boston Healthcare System and Director, Integrated Interventional Cardiovascular Program at Brigham and Women’s Hospital and the Veterans Affairs Boston Healthcare System, USA, said: ‘HYVET is a landmark study that challenges current paradigms which question the risk to benefit of treating hypertension in patients older than 80 years of age. The results of this study should encourage practitioners to treat elevated systolic blood pressure in the very elderly.’


HYVET was a randomized, double-blind, placebo-controlled trial in 3845 patients with persistent hypertension (sustained sitting systolic blood pressure ≥160 mm Hg) aged 80 years of age or older. Active treatment was indapamide sustained release (NATRILIX SR) 1.5 mg, with the addition of perindopril 2-4 mg as necessary, to reach a target blood pressure of 150/80 mm Hg. NATRILIX SR is a thiazide-like diuretic, with proven efficacy in lowering blood pressure, particularly systolic blood pressure, in the long term.3 Additionally, NATRILIX SR does not significantly affect the glucose or lipid profile over the long term.3,8 The primary study end point was fatal or nonfatal stroke.

At 2 years, mean sitting blood pressure was decreased by 15.0/6.1 mm Hg with NATRILIX SR compared with placebo. Intention-to-treat analysis showed that treatment with NATRILIX SR led to relative risk reductions of:
• 21% for total mortality (p=0.019)
• 39% for stroke mortality (p=0.046)
• 30% for stroke (p=0.055)
• 64% for heart failure (p<0.001)
• 34% for all cardiovascular events, a composite of cardiovascular causes of stroke, myocardial infarction or heart failure, (p<0.001)
Based on these findings, one death would be avoided for every 40 very elderly patients treated with NATRILIX SR (± perindopril) for 2 years.

HYVET also provided a unique opportunity to assess any effects of blood pressure–lowering treatment on cognitive function and the development of dementia in the HYVET-COG substudy. Cognitive function was evaluated using the Mini Mental Sate Examination (MMSE), with a fall to <24 or of >3 points in one year prompting assessment for possible dementia using the Diagnostic Statistical Manual edition IV, computed tomography scanning, and the Modified Ischemic Score. All cases were reviewed by an expert committee who were blinded to treatment allocation.

HYVET was stopped before follow-up for cognitive function was complete. Despite this, there was a tendency for reduction in incident dementia with active treatment (by 14%, hazard ratio 0.86, 95% CI 0.67-1.09, p=0.21), which was considered to be of clinical significance. Furthermore, when the HYVET data were added to those of previous trials using a meta-analytic technique, the result was significantly in favor of treatment (hazard ratio 0.87, 95% CI 0.76-1.00). The ongoing HYVET extension may provide supplementary data.

For further information on HYVET refer to the HYVET website:, and for information on HYVET and NATRILIX SR refer to the Servier website: or contact Servier International – 35, rue de Verdun – 92284 Suresnes Cedex – France.

1. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008;358:1887-98.
2. United Nations. World population ageing 1950-2050. IV. Demographic profile of the older population. Available from
3. Leonetti G, Emeriau J-P, Knauf H, et al. Evaluation of long-term efficacy and acceptability of indapamide SR in elderly hypertensive patients. Curr Med Res Opin 2005;21:37-46.
4. Peters R, Beckett N, Forette F, et al. Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial. Lancet 2008;7:683-9
5. American Heart Association. News release. Top research advances include studies that influence medical care, apply science to ‘real world’ communities. January 21, 2009. Available from
6. Medscape Cardiology. This Year's Awards for the Most Important Trials Go to... HYVET and ACCOMPLISH. March 2, 2009. Available from
7. Faculty of 1000 Medicine. All time Top 10 by F1000 factor. All of Medicine. March 30, 2009. Available from
8. Weidmann P. Metabolic profile of indapamide sustained-release in patients with hypertension. Drugs Safety 2001;24:1155-65.

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