Hypertension in the Very Elderly Trial (HYVET) - Protocol for the Main Trial

A number of trials and meta-analyses have demonstrated clear benefits of bl ood pressure (BP) reduction in patients aged <80 years with regard to the r eduction in stroke and cardiovascular events. However, a variety of studies have suggested that the positive relationship between BP and cardiovascula r mortality is weakened or indeed reversed in the very elderly. Most interv ention trials to date have either excluded or not recruited sufficient pati ents aged <greater than or equal to>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 greater than or equal to 8 0 years has suggested a benefit in terms of stroke reduction but has also r aised the possibility of an increase in total mortality. The benefit to ris k ratio therefore needs to be clearly established before recommendations ca n be made for treating very elderly patients with hypertension. The Hypertension in the Very Elderly Trial (HYVET) pilot recruited 1283 pat ients aged greater than or equal to 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 ph armaceutical sponsorship to run a double-blind trial. Therefore, the main t rial is a randomised, double-blind, placebo-controlled trial designed to as sess the benefits of treating very elderly patients with hypertension. It c ompares placebo with a low dose diuretic (indapamide sustained release 1.5m g daily) and additional ACE inhibitor (perindopril) therapy if required. As in the pilot trial, the primary end-point is stroke events (fatal and no n-fatal) and the trial is designed to determine whether or not a 35% differ ence occurs between placebo and active treatment. The main objective will b e achieved with 90% power at the 1% level of significance. Secondary outcom e measures will include total mortality, cardiovascular mortality, cardiac mortality, stroke mortality and skeletal fracture. 2100 patients aged greater than or equal to 80 years are to be recruited an d followed up for an average of 5 years. Entry BP criteria after 2 months o f 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 th e 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.