Discussion
Frailty as measured by the FI was a strong predictor of stroke, total mortality, and cardiovascular events in the HYVET trial, which is in agreement with multiple analyses from observational datasets [
8-
13]. We found no evidence of an interaction between baseline FI and treatment with antihypertensives on risk of stroke, death from all causes, or cardiovascular events in very elderly people. Furthermore, the burden of frailty amongst HYVET participants at baseline was similar to that seen in population studies [
13-
17].
Overall this suggests both that the HYVET population is more representative in terms of frailty than may have been supposed, and that benefits associated with blood pressure lowering treatment are accrued in both frailer and fitter older adults. These results would imply that frailty alone should not be used as a criteria for determining whether or not the treatment of an individual aged 80 and over with an antihypertensive to lower blood pressure to a goal of <150/80 mmHg is justified. Nevertheless, further work is required to fully characterize the benefit risk balance in this age group, with particular attention paid to the impact of any treatment adverse effects and/or a diagnosis of dementia, especially as there is epidemiological evidence to suggest that high blood pressure may not be harmful, and may even be beneficial, in the very elderly who are frail or have a functional disability [
24-
27]. In general, as the degree of frailty increases, so does the chance of functional impairment [
28,
29] or mobility impairment [
30]. Furthermore, as the associations between risk factors and adverse outcomes may differ at extreme age and in frailty subgroups, and be dependent on risk factor change over time, a more nuanced approach to the interpretation of results may be required.
However, our results must be interpreted with caution. The number of items (at least 30) required to complete an FI meant that, of the 3,845 participants randomized, only the 2,656 (69%) who consented to complete an additional quality of life questionnaire had sufficient data. Nevertheless, it is reassuring that those for whom an FI was not calculable differed chiefly only in relation to cognition, scoring on average one point higher on the MMSE at entry, statistically but not clinically different. It is also possible that treatment with an anti-hypertensive may have affected participant withdrawals differentially, leading to bias in our estimate of the treatment effect. However, we found no difference in withdrawal rate between the treatment groups (14.38% placebo group vs. 14.90% active treatment group) and even amongst the frailest participants (FI ≥0.35) the withdrawal rate was only 17% overall. Although only 2,656 participants were available from the HYVET trial for these analyses these data still represent a significant number of older adults.
One must also be careful not to over interpret the results from the interaction models presented in Table
3 and Figure
2. Although the estimate of the log HR decreases as FI increases for all three endpoints, the interaction term in the respective models were not significant (overall the relationship between frailty and treatment effect was not strong). Furthermore, the wider CIs in the extremes are to be expected, given that very little of our data lies in the region FI <0.1 and FI >0.4 (Figure
2).
This analysis has some strengths. In particular, the use of data from a double-blind, placebo-controlled clinical trial also allows exploration of this by randomised group providing a more robust finding that would be possible from observational data alone. The similarity of the FI at baseline with large observational datasets supports the potential applicability of the results. As far as the authors know, this is the first time the FI has been used in analysing the results of a clinical trial, particularly a hypertensive very elderly group. Although only 69% of the randomized patients were included, this still constitutes a significant number within the literature base for this age group.
Acknowledgements
Financial disclosure: This work was supported by The Dunhill Medical Trust [grant number: R287/0213] and benefited from facilities funded through Birmingham Science City Translational Medicine Clinical Research and Infrastructure Trials Platform, with support from Advantage West Midlands. The data used for these analyses comes from the HYVET study, which was funded by grants from the British Heart Foundation and the Institute de Recherches Internationales Servier, and sponsored by Imperial College London. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
All persons mentioned in the acknowledgements have given written consent. The committee members and investigators for HYVET were as follows: Co-ordinating Centre: CJ Bulpitt (lead investigator), AE Fletcher (co-investigator), NS Beckett (trial coordinator), R Peters (deputy trial coordinator), HYVET coordinating team at Imperial College London (1999 to 2008). HYVET Committees: Steering Committee: T McCormack, J Potter, BG Extremera, P Sever, F Forette, D Dumitrascu, C Swift, J Tuomilehto, J Coope (retired in 2001), C Nachev (deceased); Data Monitoring Committee: J Staessen, L Thijs, R Clarke, K Narkiewicz; End Points Committee: C Davidson (retired in 2003), J Duggan, G Leonetti, N Gainsborough, MC De Vernejoul, J Wang, V Stoyanovsky; Dementia Validation Committee: J Tuomilehto, R Clarke, A Waldman, I Walton, C Ritchie; Ethics Committee: R Fagard, J Grimley Evans, B Williams; Investigators: (*National Co-ordinators) Australia — R Warne* and I Puddey*, M Woodward, R Penhall, C Inderjeeth, S Roger, R Scholes, C Johnson; Belgium — H Celis*, G Adriaens, W Onsea, K Cornelli, D Vantroyen, P Cleen, P de Voogt; Bulgaria — C Nachev* (deceased) (national coordinator from 1998 to 2005), V Stoyanovsky* (national coordinator after 2005), P Solakov, R Prokopova, E Mantova, D Smilkova, S Mantov, K Yankulova, R Kermova, D Popov, V Sirakova, V Gergova, D Kamenova, F Grigorov, T Vassileva, R Alahverdian, M Tzekova; A Postadjian, M Geneva, V Mincheva, T Petrusheva, A Toncheva, I Gruev, V Tsanova; China — L Liu*, H Ge, S Wang, J Wang, W Zhang, S Jin, L Ge, YF Lu, S Ma, L Shen, J Guo, Z Lv (deceased), R Huang, X Li, B Guo, GE Yuan, T Zhang, L Zhang, J Feng, Z He, J Wang, L Deng, L Liu, Q Yuan, F Zhang, H Li, D Wang, K Yang, M Sun, H Liu, X Yan, F Ren, J Tang, M Zhao, X Luo, H Zhou, H Sang, J Wang, L Yan, Z Wang, J Zhang, C Wang; Finland — R Antikainen*, T Strandberg, T Konttila, A Hynninen, M Jääskivi, J Airas, T Jääskeläinen, J Tuomilehto, H Litmanen, T Karhi, H Yliharsila; France — F Forette*, J Doucet, J Belmin, A Benetos, G Berrut, T Boge, M Bonnefoy, A Carre, N Charasz, J Covillard, T Dantoine, M Escande, Y Frances, R Joire, C Jeandel, S Legrain, A Lion, M Maillet-Vioud, JP Escaillas, S Meaume, P Pfitzenmeyer, F Puisieux, E Quercy, O Rodat, J Soubeyrand, B de Wazieres, H Hindennach, L Lugassy, J Rossi, M Martel, J-M Paladel, C Ravier, A Visconti, JP Gallet, D Zygouritsas, D Charles, F Flamand, G Grandmottet, M Grandmottetegermann, C Gevrey, PL Mesnier, G Robert, C Besset-Prat, A Brousse, P Lafont, J Morelli, P Vernede, A Volkmann, X Bodin, B Destrube, R Eoche, A Boye, F Seropian, P Gernigon, D Meker, J Thomere, Y Thual, F Volny, E Grassart, M Herent, D Lejay, J-P Lopez, B Mannessier, G Pruvost, J-C Urbina; Ireland — J Duggan*; New Zealand — C Anderson*, S Lillis, J Gommans, H Senior; Poland — T Grodzicki*, Z Chodorowski, Z Gaciong; Romania — D Dumitrascu*, M Comsa, V Sandru, G Prada, M Dunca-Moisin, D Jianu, D Jinga-Lazar, V Enachescu, C Zaharia; Russia — Y Nikitin*, A Kirichenko, L Olbinskaya, A Martynov, V Zadionchenko, V Moiseev, G Storohzakov, S Nedogoda, RS Karpov, O Barbarash, G Efremushkin, V Kostenko, M Boyarkin, S Churina, T Tyurina, M Ballyuzek, L Ermoshkina, A Timofeev, S Yakusheva, N Shilkina, V Barbarich, L Latunceva, S Burakova, T Ripp, S Pekarsky, V Mordovin; Tunisia — A Belhani*, E Boughzela, S Soraya, B Youssef-Zouari, AB Khalfallah, MH Houman, AK Abida; United Kingdom — C Rajkumar*, M Wilkins, ND Pandita-Gunawardena, J Potter, E Ekpo, M Price, N de Kare-Silver, A Starczewski, S Chandran, N Nasar, M Datta-Chaudhuri, T McCormack, N Majmudar, A Gordon, L Brawn, T Solanki, F Dockery, R Schiff.
We wish to acknowledge the work of Professor C Nachev (Steering committee member, National Co-ordinator of Bulgaria and HYVET investigator from 1998 until his death in 2005).