The HY pertension in the V ery E lderly T rial – latest data

1. TheHYpertensionin the VeryElderlyTrial – latest data Stephen Jackson Professor of Clinical Gerontology King’s Health Partners

2. Declarations • First author – Nigel Beckett – has moved from Imperial College to King’s Health Partners since the NEJM paper was published. • As a PROGRESS investigator, Servier have funded speaking at meetings around 2001-3.

4. Blood Pressure & The Very Elderly (aged 80 or more) Population studies suggest better survival with higher levels of blood pressure Worse survival reported in hypertensives with SBP levels below 140 mmHg (Oates et al. 2007) Clinical trials recruited too few. Meta-analysis (n=1670) (Gueyffier et al. 1997) 36% reduction in the risk of stroke (BENEFIT) 14% (p=0.05) increase in total mortality (RISK) Hypertension in the Very Elderly Trial (HYVET) pilot results (n=1273) similar to meta-analysis (Bulpitt et al. 2003)

5. The Trial: International, multi-centre, randomised double-blind placebo controlled Inclusion Criteria:Exclusion Criteria: Aged 80 or more, Standing SBP < 140mmHg Systolic BP; 160 -199mmHg Stroke in last 6 months + diastolic BP; <110 mmHg, Dementia Informed consent Need daily nursing care Primary Endpoint: All strokes (fatal and non-fatal) Target blood pressure 150/80 mmHg

6. Statistical Analysis Numbers based on a 35% reduction in all strokes α= 0.01 ß=0.1 Stroke event rate of 40/1000 10,500 years of follow-up required 3 interim analyses planned Stopped at 2nd as decrease in stroke and all-cause mortality ITT and PP analyses Other main trial endpoints: total mortality, cardiovascular mortality, cardiac mortality, stroke mortality, heart failure

7. 4761 Entered into Placebo Run-in 916 not randomised Placebo 1912 Active 1933 • 3845 randomised; Western Europe (86) Eastern Europe (2144), China (1526), Australasia (19), Tunisia (70) • At end of trial; 1882 still in double blind, 17 vital status not known, 220 in open follow-up

8. Baseline data ‡ Fall in SBP ≥ 20mmHg and/or fall in DBP ≥ 10mmHg

9. Baseline Data (Previous Cardiovascular History)

10. Baseline data (Cardiovascular Risk factors)

11. Blood pressure separation 15 mmHg Median follow-up 1.8 years 6 mmHg

12. All stroke (30% reduction) Placebo P=0.055 Indapamide SR ±perindopril Placebo IndapamideSR ±perindopril

13. Total Mortality (21% reduction) Placebo P=0.019 Indapamide SR ±perindopril Placebo IndapamideSR ±perindopril

14. Fatal Stroke (39% reduction) Placebo Indapamide SR ±perindopril P=0.046 Placebo IndapamideSR ±perindopril

15. Heart Failure (64% reduction) Placebo P<0.0001 IndapamideSR ±perindopril Placebo IndapamideSR ±perindopril

16. 0.1 0.2 0.5 0 2 ITT – Summary

17. Biochemical Changes from Baseline (2 year cohort) • In 2 year cohort there were no significant differences between the groups with regard to change in serum…. • Potassium • Uric acid • Glucose • Creatinine • At 2 years 73.4% on combination treatment in active group (85.2% placebo)

18. Safety Reported serious adverse events (after randomisation) 448 in the placebo group vs 358 in active (p=0.001) Only 5 categorised by the local investigator possible SADRs (3 in placebo group, 2 being in active)

19. Points worthy of comment • 4 centres closed in first year due to data quality uncertainties • Large large number of patients from Eastern Europe and China • Change in shygs (Hg to semiautomatic) • Protocol change from DBP 90-109 extended to DBP<110 after 2 years • Trial stopped early due to mortality benefit in active treatment group. Last visit 8 months later. • 2nd interim analysis after 6 years of recruitment • RR stroke 0.59 (0.4-0.88) p=0.0009 • RR all cause mortality 0.76 (0.62-0.93) p=0.007 • Final dataset failed to show primary outcome benefit (all stroke)

20. Applicability

21. Achievements of HYVET test • 2008 Trial of the Year awarded by ImpACT (Important Achievements of Clinical Trials) • American Heart Association top ten list for major advances in heart disease and stroke research in 2008

22. Other findings from HYVET (1) The effect of treatment based on a diuretic (indapamide) ± ACE inhibitor (perindopril) on fractures in the HYVET. • 102 reported fractures in 3,845 participants, 90 validated (majority femur) • 38 active • 52 placebo • Cox proportional hazard regression adjusted for baseline risk factors • Point estimate 0.58 (0.33-1.00) p=0.0498 Peters et al Age Ageing 2010 39: 609-616

23. Other findings from HYVET (2) HYVET-COG • 3336 pts mean follow up 2.2 years • Baseline and annual MMSE • Diagnosis of dementia using standard criteria • MMSE • -1.1 placebo • +0.7 active • Dementia • Placebo 38 cases/1000 pt years • Active 33 cases/1000 pt years Peters et al 2008 Lancet Neurology 7: 683-689.

24. Other findings from HYVET (3) Depression: • 2656 pts completed a GDS-15 • GDS ≥ 6 associated with • risk of all cause mortality HR 1.8 (1.4 – 2.3) • CV mortality HR 2.1 (1.5 – 3.0) • All stroke HR 1.8 (1.2 – 2.8) • CV events HR 1.6 (1.2 – 2.1) • Each point on GDS at baseline associated with significantly increased risk of fatal and non fatal CV events, all cause mortality and dementia. Peters et al 2010 Age Ageing 39: 439-445

25. Conclusions • Antihypertensive treatment based on indapamide (SR) 1.5mg (± perindopril) reduced stroke mortality and total mortality in a very elderly cohort. • NNT (2 years) = 94 for stroke and 40 for mortality • Large and significant benefit in reduction of heart failure events and for combined endpoint of cardiovascular events • Benefits seen early • Treatment regimen was safe • Protocol target of <150/80 mmHg • reached in 20% on placebo; 48% on active treatment • ISH target reached in 71% (J Hum Hypertens 2011)

28. Per-Protocol