The US population aged 75 years or more has

551 Blood Pressure Chage ad Survival After Age 75 Robert D. Lager, Michael H. Criqui, Elizabeth L. Barrett-Coor, Melville R. Klauber, Theodore G. Gaiats Higher diastolic pressure predicted better survival i me 75 years or older i two prior aalyses i the Racho Berardo populatio. Diastolic chage was implicated as a possible explaatio. We studied this by assessig survival accordig to blood pressure chage i 795 me ad wome aged 75 years ad older at the time of a secod measuremet take a average of 11 years after the first, who were the followed for 5 years. Sex-specific aalyses compared participats with a diastolic decrease of 5 mm Hg or greater ad participats with a systolic decrease of 10 mm Hg or greater with those whose blood pressure levels did ot chage or icreased. I me, after adjustmet for baselie pressure, a decrease i diastolic pressure of 5 mm Hg or greater was associated with higher all-cause mortality (relative risk, 2.33; 95% cofidece iterval, 1.39 to 3.91) ad cardiovascular mortality (3.13,1.47 to 6.66). The mortality risk was strogest i me who took atihypertesive medicatio ad had a fall i diastolic pressure (1233,2.73 to 55.72) compared with treated me whose pressures did ot decrease. Amog me with isolated systolic hypertesio, those treated whose diastolic pressure remaied stable had the best survival. A systolic fall i me ad a decrease i either diastolic or systolic i wome was ot associated with poorer survival after adjustmet for baselie pressure. We coclude that a fall i diastolic pressure of 5 mm Hg was associated with poor survival i me after age 75. This risk was strogest i me who took atihypertesive medicatio. (Hypertesio. 1993;22:551-559.) KEY WORDS blood pressure cardiovascular diseases atihypertesive agets survival elderly The US populatio aged 75 years or more has bee projected to grow by 29% betwee the years 1989 ad 2000.» Little is kow about the relatios betwee traditioal cardiovascular risk factors ad survival at these ages, but a few studies have foud surprisig cotrasts i survival associatios i the very old compared with youger people. 26 People age at differet rates, ad "elderly" populatios havig a lower age limit of 70 years or youger probably iclude two groups those whose physiology remais similar to middle-aged adults ad those who are biologically older. There are sex differeces as well, at least with regard to cardiovascular agig, i which wome seem to age more slowly tha me. Adequate umbers of the very old ad attetio to possible sex differeces are prerequisites for the evaluatio of potetial cotrasts i risk factor-survival associatios i people of advaced age. Take from this perspective, extrapolatio of studies of "the elderly" to the very old may be complicated by the cotributios of "youger" elderly whose physiology may more closely resemble that of middle-aged people ad who ofte comprise most of the sample. Also, if iteractios are preset, adjustmet for age, sex, or both may ot Received October 19, 1992; accepted i revised form Jue 15, 1993. From the Departmet of Family ad Prevetive Medicie, Uiversity of Califoria, Sa Diego, School of Medicie, La Jolla. Correspodece to Robert D. Lager, MD, MPH, Divisio of Epidemiology, UCSD School of Medicie, La Jolla, CA 92093-0607. provide accurate estimates of risk associatios. Multivariate aalyses may mask the true relatio if there are opposig effects i two or more subgroups. This may explai the disparity i risk factor associatios reported i the "elderly" usig data from cohorts that have differet age ad sex distributios. We have previously reported that me aged 75 years ad older with higher diastolic blood pressure (DBP) had better survival rates tha me at these ages with lower DBP. 2 This relatio was liear, ad we foud o threshold for DBP below which this effect disappeared. Results i wome ad youger me showed the covetioal associatio, with poorer survival at higher blood pressures. These fidigs were cosistet with results from aother study i a differet cohort. 3 Aalyses to look for factors that could explai the pheomeo of poorer survival i me with lower DBP, icludig use of atihypertesive medicatio, history of hypertesio, history of coroary disease, isolated systolic hypertesio (ISH), blood lipids, blood glucose, smokig, obesity, ad chage i DBP (as a cotiuous variable), failed to provide a explaatio. 7 The Established Populatios for Epidemiologic Studies of the Elderly (EPESE), which erolled me ad wome aged 65 years ad older i three commuities, also reported this associatio betwee lower DBP ad mortality through 5 years of follow-up i oe of three cohorts (East Bosto) but foud that it disappeared after 2 years i the other two populatios. 5 The preset aalysis was desiged to assess whether a cliically sigificat fall i either or both compoets of

552 Hypertesio Vol 22, No 4 October 1993 TABLE 1. Number of Participats, Percet All-Cause ad Cardiovascular Disease Mortality, ad 11-Year Mea Blood Pressure Chage Accordig to Blood Pressure Chage Category Me Wome Chage Category SBP Decrease a 10 mm Hg Decrease 0 to 10 mm Hg No chage or icrease Total DBP Decrease 5 mm Hg Decrease 0 to 5 mm Hg No chage or icrease Total 96 61 249 406 221 50 135 406 (%) (23.6) (15.0) (61.3) (54.4) (12.3) (33.3) % Mortality 34.4 29.5 26.1 28.6 34.8 30.0 17.8 28.6 %CVD Mortality 24.1 12.2 15.3 17.0 23.4 12.5 8.3 17.0 Mea (SE) BP Chage -23.9-4.6 18.2 4.8-14.6-2.6 6.8-6.0 (14.5) (2.4) (13.8) (22.0) (8.0) (1.2) (6.1) (12.0) 63 43 279 385 212 48 125 385 (%) (16.4) (11.2) (72.5) (55.1) (12.5) (32.5) % Mortality 28.6 16.3 12.9 15.8 16.0 12.5 16.8 15.8 %CVD Mortality 19.6 12.2 7.3 9.7 9.6 10.6 9.6 9.7 Mea (SE) BP Chage -22.6-4.3 21.9 11.7-14.7-2.5 7.4-6.0 CVD idicates cardiovascular disease; SBP, systolic blood pressure; ad DBP, diastollc blood pressure. Number of participats for CVD mortality aalyses (348 me ad 359 wome) was smaller tha for all-cause mortality because subjects with ocardiac causes of death were excluded. Data are for me ad wome aged 75 years ad older at the 1984-1987 visit (10.9) (2.4) (18.7) (23.9) (7.5) (1.1) (9.9) (12.8) blood pressure durig a 11-year iterval was associated with poorer survival i a subsequet 5-year follow-up period i me ad wome aged 75 years or older ad to evaluate whether the use of atihypertesive medicatio iflueced this risk. Methods Betwee 1972 ad 1974 all adult residets of Racho Berardo, Calif, were ivited to participate i a Lipid Research Cliic (LRC) Prevalece Study. Eighty-two percet of the target populatio 40 through 79 years of age (=4382) participated. Blood pressure was obtaied usig a cliical protocol after the participat had bee seated for at least 5 miutes. A subsequet visit (visit 2) was coducted a average of 6 moths later i a 15% radom sample of the origial populatio. Visit 2 blood pressures were take accordig to the Hypertesio Detectio ad Follow-up Program (HDFP) protocol. 8 Durig 1984-1987, 2480 of the 3431 survivig members of the origial cohort iitially aged 40 through 79 years retured for aother evaluatio for chroic diseases. The 388 wome ad 407 me who were at least 65 years old at the 1972-1974 visit (ad thus were 75 years or older by 1984-1987) ad who retured durig 1984-1987 costituted the populatio for the preset study. Of these participats, oe ma ad three wome were excluded for a missig blood pressure measuremet. Blood pressure at the latter visit was measured usig the HDFP protocol. Iterval blood pressure chage was calculated by subtractig the blood pressure at the 1972-1974 visit from the 1984-1987 measuremet. For may of these older subjects, the DBP chage was a egative umber owig to a tred for lower DBP with icreasig age i the elderly. A additioal populatio composed of all 895 me aged 50 through 69 years at the 1984-1987 visit was used as a youger compariso group for these aalyses. All participats provided iformed coset at each visit, ad the study protocols were approved by the Uiversity of Califoria, Sa Diego, Committee o Ivestigatios Ivolvig Huma Subjects. Cliically relevat categories for DBP chage were defied as (1) o chage or icrease, (2) less tha 5 mm Hg decrease, ad (3) greater tha or equal to 5 mm Hg decrease. Parallel groups for systolic blood pressure (SBP) were based o a iterval chage of 10 mm Hg. At the 1984-1987 visit, all curretly used medicatios were recorded ad validated by checkig prescriptios or cotaiers. ISH was deed as SBP greater tha or equal to 160 mm Hg ad DBP less tha 90 mm Hg. Vital status was obtaied yearly ad was kow for a average of 5 years beyod the 1984-1987 visit for all participats. Cardiovascular disease (CVD) deaths were those assiged ICD-9 codes 400 through 438 by a certified osologist. Associatios betwee risk factors ad survival were tested usig proportioal hazards regressio ad Kapla-Meier procedures. Aalyses were performed usig EPILOG PLUS statistical software (Epiceter Software, Pasadea, Calif). All P values are two-tailed. Results Mea SBP icreased i both sexes (by 4.8 mm Hg i me ad 11.7 mm Hg i wome), ad mea DBP decreased (by 6.0 mm Hg i both me ad wome). As show i Table 1, less tha a quarter of me ad wome had a fall i SBP of 10 mm Hg or greater, but more tha half had a decrease i DBP of 5 mm Hg or greater over the average 11-year iterval betwee the two measuremets. Withi the three chage categories for each blood pressure measuremet, the mea iterval chage i blood pressure was similar i me ad wome. Durig the 5-year follow-up period, 28.6% of me ad 15.8% of wome died; approximately 60% of these were CVD deaths (Table 1). Table 2 shows age-adjusted relative risks from proportioal hazards regressio models for all-cause ad CVD mortality for each sex. Results are show for all people of each sex ad are stratified o the use of

Loger et al Blood Pressure ad Survival After Age 75 553 TABLE 2. Age-Adjusted Relative Risks From Proportioal Hazards Regressio by Sex for All Participats ad Stratified by Use of Atihypertesive Medicatio at the Later Visit Me Wome* Model Age+SBP chage group All-cause mortality A-ARR (P) 95% Cl CVD mortality A-ARR (P) 95% Cl Age+DBP chage group All-cause mortality A-ARR (P) 95% Cl CVD mortality A-ARR (P) All Me 1.35 (.16) 0.88-2.08 1.54 (.14) 0.87-2.72 2.13 (.00) 1.34-3.38 2.93 (.00) Nouser 1.62 (.12) 0.88-3.00 2.43 (.02) 1.16-5.12 1.71 (.06) 0.97-3.02 2.42 (.03) 95% Cl 1.47-5.86 1.08-5.43 0.90-17.31 0.48-2.13 0.21-2.47 0.31-2.19 SBP idicates systolic blood pressure; A-ARR, age-adjusted relative risk; Cl, cofidece iterval; CVD, cardiovascular disease; ad DBP, diastolic blood pressure. Data are for SBP decrease of 210 mm Hg vs o chage or Icrease or DBP decrease of a5 mm Hg vs o chage or Icrease, me ad wome aged 75 years ad older at the 1984-1987 visit. Results for wome were uchaged by the additio of estroge use to the model. User 1.07 (.85) 0.54-2.11 0.69 (.44) 0.27-1.76 7.12 (.01) 1.70-29.90 3.95 (.07) All Wome 2.28 (.00) 1.2&4.02 2.83 (.01) 1.34-5.95 0.94 (.83) 0.55-1.62 1.01 (.98) Nouser 1.92 (.30) 0.55-6.62 4.08 (.05) 1.02-16.34 0.66 (.36) 0.27-1.62 0.72 (.60) User 1.50 (.26) 0.74-3.04 1.73 (.24) 0.69-4.30 0.77 (.50) 0.37-1.61 0.82 (.70) atihypertesive medicatio. I each model the referece group cosists of people with the same exposure but who had o chage or a icrease i blood pressure. I all me, these aalyses showed a sigificat excess risk associated with a decrease i DBP of at least 5 mm Hg for both all-cause mortality (age-adjusted relative risk [A-ARR], 2.13; 95% cofidece iterval [Cl], 1.34 to 3.38) ad CVD death (A-ARR, 2.93; 95% Cl, 1.47 to 5.86). This relatio was much stroger i me who took atihypertesive medicatios tha i me who did ot. Me who took atihypertesive drugs ad had a drop i DBP of 5 mm Hg or greater were more tha seve times more likely to die (A-ARR, 7.12; 95% Cl, 1.70 to 29.90) tha me who also took these drugs but did ot experiece a drop i DBP. These me also had a icreased risk of CVD death but at a margial level of statistical sigificace (A-ARR, 3.95; 95% Cl, 0.90 to 17.31). A quadratic term for DBP chage was ot statistically sigificat i ay model for all me or for the subgroups defied by medicatio use. I me, oe of the hazard estimates for a decrease of at least 10 mm Hg i SBP were statistically sigificat i models for all-cause mortality. With stratificatio o use of atihypertesive medicatio, there was a associatio betwee a 10 mm Hg fall i SBP ad CVD mortality that was limited to me who did ot take atihypertesive medicatio. A similar associatio was ot foud for all-cause mortality. I wome, there was o associatio betwee a fall i DBP ad mortality, or was there ay differece i these DBP associatios accordig to use of atihypertesive medicatio. A relatio betwee SBP chage ad mortality was see i wome; a drop of at least 10 mm Hg i SBP was associated with a icreased risk of death from all causes (A-ARR, 2.28; 95% Cl, 1.29 to 4.02) ad CVD death (A-ARR, 2.83; 95% Cl, 1.34 to 5.95). The risk of CVD death was greatest for wome who did ot use atihypertesive medicatios. Results for wome were uchaged by the additio of estroge use to the models. To accout for regressio to the mea ad/or severity of hypertesio at baselie, we repeated these aalyses with adjustmet for baselie blood pressure. Results of these models are preseted i Table 3. Accoutig for baselie blood pressure reduced all associatios betwee a drop i SBP ad death i both sexes to levels that were ot statistically sigificat. I wome, DBP chage remaied uassociated with mortality after adjustmet for baselie DBP. By cotrast, i me, the risk associated with the use of atihypertesive drugs early doubled compared with models ot adjusted for baselie DBP (A-ARR, 12.33; 95% Cl, 2.73 to 55.72 for all-cause mortality, ad A-ARR, 7.43; 95% Cl, 1.51 to 36.58 for CVD death). Thus, after adjustmet for regressio to the mea ad the iitial severity of hypertesio, oly a fall i DBP i me remaied a sigificat predictor of death. Subgroup aalyses showed this effect to be cocetrated i me who took atihypertesive medicatios. As i the more basic models, quadratic terms for DBP chage i these multiply adjusted models were ot sigificat. The Figure cotrasts the relative risks of mortality, after adjustmet for baselie DBP, i me who had a iterval fall of at least 5 mm Hg i DBP compared with me who had o chage or a icrease i DBP. Poit estimates are show for all me ad are stratified o the use of atihypertesive medicatios. Aalyses were repeated for the subset of 259 participats who had blood pressure measured by the stadardized HDFP method at both visit 2 (approximately 6

554 Hypertesio Vol 22, No 4 October 1993 TABL 3. Age-Adjusted Relative Risks From Proportioal Hazards Regressio by Sex for All Participats ad Stratified by Use of Atlhypertesive Medicatio at the Later Visit With Adjustmet for Baselie Blood Pressure Model Age+SBP chage group All-cause mortality A-ARR (P)+SBP 95% CI+SBP CVD Mortality A-ARR (P)+SBP 95% CI+SBP Age+DBP chage group All-cause mortality A-ARR (P)+DBP 95% CI+DBP CVD mortality A-ARR (P)+DBP 95% CI + DBP All Me 1.27 (.36) 0.76-2.13 1.37 (.37) 0.69-2.75 2.33 (.00) 1.39-3.91 3.13 (.00) 1.47-6.66 Me Nouser 1.36 (.40) 0.66-2.80 1.88 (.17) 0.7&4.66 1.89 (.05) 0.99-3.60 2.41 (.06) 0.97-5.96 User 1.00 (.99) 0.47-2.17 0.76 (.61) 0.27-2.16 12.33 (.00) 2.73-55.72 7.43 (.01) 1.51-36.58 All Wome 1.39 (.33) 0.72-2.68 1.67 (.24) 0.72-3.89 0.87 (.67) 0.46-1.63 0.79 (.59) 0.34-1.86 Wome* Nouser 1.81 (.40) 0.46-7.18 3.03 (.19) 0.58-15.78 0.95 (.93) 0.33-2.72 0.71 (.63) 0.17-2.91 User 0.95 (.89) 0.43-2.09 1.27 (.66) 0.45-3.60 0.71 (.42) 0.31-1.64 0.74 (.59) 0.24-2.22 SBP idicates systolic blood pressure; A-ARR, age-adjusted relative risk; Cl, cofidece iterval; CVD, cardiovascular disease; ad DBP, diastollc Wood pressure. Data are for SBP decrease of ^10 mm Hg vs o chage or icrease or DBP decrease of a5 mm Hg vs o chage or icrease, me ad wome aged 75 years ad older at the 1984-1987 visit. Results for wome were uchaged by the additio of estroge use to the model. moths after visit 1, the primary 1972-1974 visit) ad the 1984-1987 visit to see if variatio i the blood pressure measuremet due to the differece i method explaied these fidigs. The correlatio betwee DBP measured i me at visit 1 ad visit 2 was.56. For SBP measuremets i me, the correlatio was.53. I wome, the correspodig values were.39 ad.42. All survival treds remaied qualitatively idetical whe visit 2 data were used as the baselie istead of visit 1 data (results ot show). To test whether this associatio was preset i youger me, we repeated these aalyses i the 895 me of this cohort aged 50 through 69 years at the later visit. Before adjustmet for baselie blood pressure, there were margial elevatios i the risk associated with a decrease i DBP of 5 mm Hg or greater for all causes (A-ARR, 1.48; 95% CI, 0.98 to 2.25) ad CVD mortality (A-ARR, 1.76; 95% CI, 0.95 to 3.30). A decrease i SBP of 10 mm Hg or greater was weakly associated with all-cause mortality (A-ARR, 1.36; 95% CI, 0.88 to 2.10) ad more strogly related with CVD death (A-ARR, 1.87; 95% CI, 1.02 to 3.44). After adjustmet for baselie blood pressure, oe of these fidigs remaied statistically sigificat. I models stratified o atihypertesive drug use at the recet visit, the oly sigificat fidig was for a icreased risk of CVD death i me with a SBP drop who did ot take atihypertesive drugs (A-ARR, 2.62; 95% CI, 1.08 to 6.34, with adjustmet for baselie SBP, ad A-ARR, 3.76; 95% CI, 1.73 to 8.20, without adjustmet). Thus, patters i these youger me differed from those observed i the oldest me, as did the patters see i the oldest wome. We ext cosidered whether the duratio of atihypertesive therapy iflueced this associatio i me. Table 4 shows the umber ad percet (crude) mortality for me by DBP chage category ad atihypertesive medicatio use status at the two cliic visits. Amog me who were o these drugs at both visits, those who had a iterval drop i DBP of at least 5 mm Hg had 12J3 All Me No-Users Users Bar graph shows relative risks for death, adjusted for age ad baselie diastolic blood pressure (DBP) i all me ad by use of atihypertesive medicatio for iterval chage i DBP of 5 mm Hg or greater vs o chage or icrease i DBP. CVD idicates cardiovascular disease. AU Cause Mortality CVD Mortality

hager et al Blood Pressure ad Survival After Age 75 555 TABLE 4. Atihypertesive Medicatio Use Patter at Each Visit by Dlastollc Blood Pressure Chage Category ad Crude Mortality DBP Chage Category Decrease 5 mm Hg Decrease 1 to 5 mm Hg No chage or icrease Total 102 20 81 203 No/No % Mortality 36.3 20.0 21.0 28.6 4 1 2 7 Yes/No % Mortality 50.0 100.0 50.0 57.1 52 12 16 80 No/Y«s % Mortality 36.5 25.0 12.5 30.0 32 8 13 53 Yes/Yes % Mortality 43.7 37.5 0.0 32.1 DBP idicates diastolic blood pressure. Atihypertesive medicatio use patter was ukow for 63 me, 14% of the decrease a5 mm Hg group, 18% of the decrease 1 to 5 mm Hg group, ad 17% of the o chage or icrease group. Data are for me aged 75 years or older at the 1984-1987 visit. the greatest percet mortality. Noe of the me who were o treatmet at both visits but maitaied their DBP at or above the baselie level died. I me who started takig these drugs durig the iterval betwee cliic visits, those who experieced a fall i DBP of 5 mm Hg or greater had poorer survival tha me with similar exposure whose DBP decreased less or icreased. Me who did ot take atihypertesive drugs at either visit but who had a drop i DBP of 5 mm Hg or greater also had poorer survival tha me whose DBP levels were preserved or icreased. We compared the mortality risk i me with a DBP fall of 5 mm Hg or greater i each of the four categories of atihypertesive use with the mortality risk i me who did ot take atihypertesive medicatio at either visit ad who had o chage or a icrease i DBP over the iterval. Atihypertesive use at these two visits was coded as No/No, Yes/No, No/Yes, ad Yes/Yes. Models were adjusted for age ad baselie DBP. The A-ARR for the No/No patter was 2.24 (95% CI, 1.19 to 4.19); for Yes/No, 3.97 (95% CI, 0.89 to 17.77); for No/Yes, 2.95 (95% CI, 1.30 to 6.68); ad for Yes/Yes, 3.45 (95% CI, 1.47 to 8.08). The two classes of medicatio that accouted for early all use were diuretics ad /3-blockers. Separate aalyses limited to users of each class of medicatio showed idetical effects for both, although the results i these subgroups were ot statistically sigificat because of the small umber of me i each category. To test the possibility that fallig DBP was simply a marker for poor global health status that was associated with early mortality, we repeated all the above models for me elimiatig the 61 subjects who died i the first 2.5 years (the first half of the follow-up iterval). Results based o the remaiig 55 deaths, icludig those stratified o medicatio use, were strogly cocordat with the estimates for the etire 5-year follow-up period. For all me aged 75 years or older, a decrease i DBP of 5 mm Hg or greater compared with o chage or a icrease was associated with a A-ARR for all-cause mortality of 1.95 (95% CI, 1.11 to 3.44). For users of atihypertesive medicatio, the correspodig A-ARR was 5.99 (95% CI, 1.37 to 26.19), ad for me who did ot take atihypertesive medicatio, the A-ARR was 1.77 (95% CI, 0.85 to 3.68). These results from the latter 2.5 years of the follow-up iterval ca be compared with the 5-year estimates show i Table 2. I models accoutig for baselie DBP that correspod to the results show i Table 3, the A-ARR for all-cause mortality before stratificatio o atihypertesive use was 2.16 (95% CI, 1.14 to 4.09); for users of atihypertesive medicatio, the A-ARR was 8.79 (95% CI, 1.75 to 44.00), whereas for me who did ot take atihypertesive medicatios, the A-ARR was 1.98 (95% CI, 0.87 to 4.52). By cotrast with DBP chage ad cosistet with results for the etire follow-up period, a SBP decrease of 10 mm Hg or greater i the latter 2.5 years of follow-up was ot sigificatly associated with death i ay subgroup. Aalyses limited to the first 3 years of the follow-up iterval (ot show) likewise yielded idetical treds. Because most hypertesio i the very old is ISH, we ivestigated these associatios by ISH status. Atihypertesive treatmet was weakly protective i me aged 75 years or more with ISH (A-ARR for all-cause mortality, 0.74; 95% CI, 0.31 to 1.77, ad for CVD death, 0.65; 95% CI, 0.18 to 2.33). Because sequelae of ISH, treated or ot, could potetially explai some of the observatios regardig blood pressure chage, categorical aalyses were doe separately for me with ad without ISH. After adjustmet for baselie DBP, the A-ARR associated with a drop i DBP of 5 mm Hg or greater for me without ISH was 1.79 (95% CI, 0.99 to 3.20) for all-cause mortality ad 2.99 (95% CI, 1.23 to 7.26) for CVD death. For me with ISH, the correspodig A-ARR values were 6.98 (95% CI, 2.14 to 22.78) for all-cause mortality ad 5.43 (95% CI, 1.25 to 23.62) for CVD mortality. To assess how this chage i DBP was reflected i survival of me treated ad ot treated for ISH, we further evaluated these associatios i models stratified o both atihypertesive use at the later visit ad ISH. These results are displayed i Table 5. Because 54 me with ucertai medicatio status were excluded, the poit estimates for me with ad without ISH give i the paragraph above do ot reflect the middle of the two categories for each show i Table 5. The crude rates ad the multiply adjusted poit estimates from these strata idicate that me who did ot have ISH but who took atihypertesive medicatio ad had a decrease i DBP of 5 mm Hg or greater had a substatially icreased risk of death, although statistical power was compromised by small umbers, ad cofidece limits were wide (A-ARR, 13.71; 95% CI, 1.67 to 112.49 for all-cause mortality). Amog me with ISH, the relative risk of death i those who took atihypertesive medicatio ad had a decrease i DBP of 5 mm Hg or greater, compared with me with ISH who also took

556 Hypertesio Vol 22, No 4 October 1993 TABLE 5. Percet Mortality ad Adjusted Relative Risks for All-Cause ad Cardiovascular Mortality Accordig to Isolated Systolic Hypertesio Status ad Atlhyperteslve Medicatio Use ISH No Yes No Yes Atlhyperteslve Medicatio No No Yes Yes DBP Decrease a5 mm Hg 81 (33.3) 25 (48.0) 54 (35.2) 30(46.7) (% Dead) No Chage or Icrease I DBP 72 (22.2) 11 (18.2) 22 (4.5) 7(14.3) Adjusted Relative Risk (P) ad 95% Cl All-Cause Mortality Base Model* 1.45 (.31) 0.71-2.98 15.32 (.01) 2.04-115.22 13.71 (.01) 1.67-112.49 8.80 (.05) 0.97-79.68 +Iterval SBP Chagtf 1.25 (.56) 0.59-2.67 17.60 (.01) 2.01-153.90 15.09 (.01) 1.75-130.32 27.35 (.01) 2.10-356.31 Base Model* 2.22 (.13) 0.78-6.29 9.90 (.05) 0.96-101.96 9.55 (.04) 1.07-85.52 4.26 (.26) 0.35-52.01 CVD Death + Iterval SBP Chaget 1.88 (.26) 0.63-5.63 7.13 (.12) 0.60-84.75 10.97 (.04) 1.17-102.95 547.25 (.02) 3.25 ISH idicates isolated systolic hypertesio; Cl, cofidece iterval; DBP, dlastollc blood pressure; SBP, systolic blood pressure; ad CVD, cardiovascular disease. Data are for me aged 75 years or older at the 1984-1987 visit. *Base model was adjusted for age ad baselie DBP. tadjusted for age, baselie DBP, ad iterval SBP chage. these drugs but had o chage i DBP, was 8.80 (95% Cl, 0.97 to 79.68). The relative risk was stroger, at 15.32 (95% Cl, 2.04 to 115.22), i me with ISH who were ot treated with medicatio but had a decrease i DBP of 5 mm Hg or greater compared with utreated me with ISH whose DBP did ot fall. Because treatmet for ISH may reduce both compoets of blood pressure, we estimated the relative risks associated with a decrease i DBP of 5 mm Hg or greater i the ISH/medicatio categories with further adjustmet for the iterval chage i SBP (Table 5). With this adjustmet, the patter related to treatmet chaged. The relative risk of death associated with a fall i DBP of 5 mm Hg or greater was higher i me who took atihypertesive drugs (A-ARR, 27.35; 95% Cl, 2.10 to 356.31) tha i me who did ot (A-ARR, 17.60; 95% Cl, 2.10 to 153.90). The coefficiet for SBP chage was egative (suggestig protectio with lowered SBP) oly i the models for me without ISH who did ot take atihypertesive medicatio. It was positive i all other models ad reached statistical sigificace oly i the model for CVD mortality i me with ISH who took atihypertesive medicatio. Because the combied effects of iterval chages i DBP ad SBP could be more importat tha either aloe, we assessed survival i these me based o categories defied with both compoets of blood pressure usig Kapla-Meier survival procedures. For all me, whe SBP did ot chage or icreased, there was a liear tred for worse survival as DBP decreased (x 2 for tred, 6.39; P^.01). Treds for DBP chage withi categories of SBP decrease from 0 to 10 mm Hg ad greater tha or equal to 10 mm Hg were ot statistically sigificat. Whe DBP chage categories were held costat to evaluate the effect of SBP chage withi each of those three levels, o SBP treds were sigificat. Amog the 76 me who had the greatest decrease i both compoets of blood pressure (SBP decrease slo mm Hg ad DBP decrease ^5 mm Hg), observed/ expected mortality was very ear uity (1.08). I cotrast, amog the 102 me who had o chage or a icrease i SBP but a decrease i DBP of greater tha or equal to 5 mm Hg, there was a 38% excess i mortality (observed/expected rate, 1.38). Aalyses restricted to me with ISH who took atihypertesive medicatio ad who had stable or icreased SBP showed a tred for poorer survival with decreasig DBP that was of borderlie statistical sigificace (=25, \ 2 for tred, P^.06). No other treds for survival by blood pressure chage categories approached sigificace i me with ISH who took atihypertesive medicatio, i part because of small umbers i some cells. All of the ie me who took atihypertesive medicatio ad had a decrease i SBP of 10 mm Hg or greater also had a decrease i DBP of 5 mm Hg or greater; three of them died. Discussio We have previously reported that lower DBP was associated with poorer survival i me aged 75 years ad older regardless of its cause. 7 The preset study shows that a fall i DBP of 5 mm Hg or greater, particularly whe associated with use of atihypertesive medicatio, represets oe meas of eterig this high-risk group. Adjustmet for baselie DBP further icreased the risk estimate associated with atihypertesive use, makig prior hypertesio ad regressio to the mea ulikely explaatios. Duratio of use of atihypertesive drugs did ot appear to affect the risk associated with this decrease i DBP, because the percetage mortality i me who were o therapy at both visits (32%) was similar to that of me who were takig medicatio oly at the secod visit (30%). It could be argued that a fall i blood pressure was associated with icreased mortality because it was a marker for decliig health. However, we have previously reported that the associatio betwee lower DBP ad mortality was ot explaied by deaths early i the follow-up period. 2 Elimiatig all deaths i the first half of the follow-up period i the preset aalysis likewise did ot alter the treds observed. Also, the lack of a threshold for this effect, as show i earlier reports of a

hager et al Blood Pressure ad Survival After Age 75 557 liear relatio betwee higher DBP ad survival i me aged 75 years or more 2-7 argues agaist major circulatory failure as the explaatio. Primary circulatory failure, rather tha a effect limited to DBP chage, also seems a ulikely explaatio, because the observed/expected mortality for me with the largest decreases i both DBP ad SBP was ear uity, whereas the ratio for those with o chage or a icrease i SBP but a drop i DBP of 5 mm Hg or greater was elevated. Further evidece agaist the hypothesis that this decrease i DBP simply represets a marker for poor health followed by early demise was provided by the strikig similarity betwee the relative risks obtaied usig oly the deaths i the secod half of the follow-up iterval ad those from models that icluded all evets. Ideed, perhaps the most compellig aspect of these data was that, regardless of the iitial visit chose (visit 1 or visit 2) ad regardless of the follow-up iterval studied (the first 3 years, the first 5 years, or the latter 2.5 years), the results were cosistet, eve to the subgroup level. Associatios betwee SBP chage ad mortality were foud primarily i wome ad were much weaker. Adjustmet for baselie SBP elimiated all relatios betwee a drop i SBP ad mortality. These results could be explaied by the severity of hypertesio at the first visit or by regressio to the mea. Use of atihypertesive medicatios did ot icrease the risk of death i wome. Results i youger me were also differet from those i me aged 75 years ad older. I me aged 50 to 69 years, o associatios remaied betwee a fall i DBP of 5 mm Hg or greater ad mortality after adjustmet for baselie DBP. Also, there were o sigificat associatios betwee atihypertesive medicatio use, a decrease i blood pressure, ad mortality i youger me. A decrease i SBP of 10 mm Hg or greater was associated with icreased mortality oly i me 50 to 69 years old ot takig atihypertesive medicatios. The results i youger me ad i wome 75 years ad older idicate that the associatios reported here for a cliically sigificat decrease i DBP are relevat oly to me aged 75 years ad older. Based o the fidig of better survival for wome with higher blood pressure i the Fiish commuity study, 3 oe might speculate that similar effects may become evidet i wome at still older ages. The age distributio of wome i our populatio does ot allow us to assess that possibility at this time. The fidig that adjustmet for baselie DBP stregtheed the risk estimate for a DBP fall associated with use of atihypertesive medicatio reiforces the thesis that higher DBP is associated with better survival i these oldest me. Without adjustmet, the protective effect associated with higher baselie DBP atteuates the risk estimate. Whe adjustmet removed that protective effect, the risk estimate doubled. O the other had, i youger me ad i wome, iitial fidigs of a possible associatio betwee a drop i SBP ad mortality were elimiated by adjustmet for baselie SBP, suggestig that there is o true physiological relatio. Rather, prior disease, regressio to the mea, or both probably explaied those uadjusted fidigs. For me 75 years or older with ad without ISH, a drop of at least 5 mm Hg i DBP was associated with poorer survival. Thus, ISH itself did ot explai these fidigs. Stratificatio o the use of atihypertesive medicatio ad ISH suggested that use of medicatio made a importat cotributio to this risk. The hazard was approximately 10 times greater i me without ISH who took medicatio ad had a decrease i DBP of 5 mm Hg or greater compared with me without ISH who did ot take medicatio but whose DBP also decreased the same amout. Few deaths occurred i the me with ISH who took medicatio ad had o chage or a icrease i their DBP. After SBP reductio was accouted for i survival models for me with ISH, a drop i DBP associated with atihypertesive treatmet carried a high risk of mortality. These results suggest that it may be safest to reduce the systolic compoet of ISH while preservig DBP i me after age 75. The participats i this study were white ad lived i a commuity of relatively high socioecoomic status with good access to health care. The prevalece of hypertesio i these me aged 75 years ad older was 34%, comparable to the 38% level i me aged 65 years ad older i the Cardiovascular Health Study. 9 Little has bee published o commuity-dwellig populatios with people i these oldest age rages. It is possible that these associatios might emerge earlier i less healthy me. O the other had, their access to health care (more tha 90% visited a doctor i the year before the study visit) could obscure a mortality differece i situatios i which cliical maagemet affects the outcome. The Systolic Hypertesio i the Elderly Program (SHEP) demostrated a reductio i combied ofatal ad fatal CVD i a cliical trial that compared atihypertesive medicatio with placebo i me ad wome aged 60 years ad older. 10 Our fidig that atihypertesive treatmet was weakly associated with improved survival i me with ISH is cosistet with those results, but our aalyses suggest that treatmet of ISH is associated with better survival i me after age 75 if DBP is preserved. I cotrastig our results with SHEP it is importat to recogize differeces i the desig of these studies. Participats i SHEP were highly selected; oly approximately 1% of those screeed etered the study, reflectig exclusio for existig disease, willigess to eter a cliical trial, ad the presece of mild to moderate ISH. By cotrast, the Racho Berardo Study is a commuity-based populatio sample. Also, although there was o age-sex iteractio for treatmet effect, SHEP reports to date have ot looked at all-cause ad CVD mortality by age- ad sex-specific subgroups. A age threshold effect like that described here could be masked by a limited cotributio of small umbers of SHEP me older tha age 75 to the test for iteractio. Thus, comparable results for me aged 75 years or more followed i SHEP are ot presetly available, ad possible iteractio by age ad sex as observed i the Racho Berardo cohort caot be evaluated. The Europea Workig Party o Hypertesio i the Elderly (EWPHE) foud that atihypertesive treatmet reduced CVD mortality i people aged 60 to 75 years, but treatmet was associated with icreased mortality i people aged 75 to 97 years." This crossover

558 Hypertesio Vol 22, No 4 October 1993 i treatmet effect at about age 75 is cosistet with our fidigs i me. However, the EWPHE study icluded wome as well, ad their mortality experiece cotributed to the excess observed after age 75. I the preset study we foud o icreased risk associated with treatmet i wome. I the East Bosto cohort of the EPESE study, 5 me ad wome aged 65 years ad older who had DBP less tha 75 mm Hg had poorer survival at 2 years tha those with higher blood pressures. Similar relatios were see i subgroups takig ad ot takig atihypertesive medicatio; but amog those who took medicatio, moderate DBP (75 to 89 mm Hg) was associated with slightly better survival tha high DBP (90 mm Hg or greater). These fidigs are cocordat with our preset report to the extet that lower DBP was associated with poorer survival i subjects both o ad off blood pressure treatmet. However, data o blood pressure chage were ot reported, so direct compariso with the preset aalyses caot be made. I the other two EPESE populatios, higher DBP was associated with poorer survival amog those takig atihypertesive medicatios but ot i participats who did ot take these drugs. Results were ot reported by age or sex. Give the differig effects by age ad sex observed i the Racho Berardo populatio, it is possible that the icosistecies i the three EPESE cohorts result from age ad sex iteractios. A report from the Framigham study also foud a associatio betwee low DBP ad mortality i subjects aged 45 to 84 years ad attributed this excess risk to preexistig myocardial ifarctio. 12 We previously tested this hypothesis i the Racho Berardo populatio 7 ad foud it did ot explai the excess mortality i the oldest me with low DBP. The cosistecy of our results after early deaths were elimiated argues agaist this explaatio for the results of the preset aalysis. Agig of the cardiovascular system is associated with a umber of well-documeted chages, icludig icreased peripheral vascular resistace ad decreased vetricular ad peripheral vascular compliace. 13 The agig heart maitais cardiac output by icreasig ed-diastolic volume ad by applyig the Frak-Starlig mechaism. /J-Adreergic modulatio is also reduced. 14 I the face of reduced DBP, these agig-related chages may limit the rage of physiological adjustmet available to maitai perfusio to vital orgas, icludig the myocardium, which has little itrisic autoregulatory capability. 14 Thus, it is plausible that lower DBP i the aged cardiovascular system could be hazardous. This effect may be geeralized across major orga systems, because the risk estimates i all me for CVD mortality were similar to those for all-cause mortality. For me o atihypertesive drugs, the risk estimates for CVD mortality were uiformly lower tha for all-cause mortality, suggestig a icrease i o-cvd causes of death. The lack of a associatio i wome represets aother geder-related differece i CVD risk. Wome ted to develop CVD later tha me; that delay could also exted to physiological chages related to seescece. We curretly lack adequate umbers of wome substatially older tha these me to test the possibility that wome maifest this pheomeo later. Poorer survival with excessive lowerig of DBP i hypertesive idividuals has bee reported i several studies of youger cohorts i which a J-shaped curve betwee DBP ad survival has bee evidet. 12-15 I these populatios, subjects at both the lower ad upper rages of DBP had icreased mortality. It has bee suggested that this J-shaped relatio ca explai the poorer survival with lower DBP i elderly hypertesive subjects. 14 We looked for a J-shaped relatio usig a quadratic model but did ot fid it. However, we caot exclude the possibility that the iverse associatio we detected represets the middle ad left deflected portios of a "J" ad that the lack of very high DBP values i our cohort obscured the ascedig limb of a relatio that is shifted toward substatially elevated DBP. Alteratively, me with elevatios of DBP i the rage that could describe a "J" may have succumbed to complicatios of this coditio before reachig the ages described here. It is very likely that aother physiological epoch characterized by ormative fuctio that differs from that i youger people begis at a age beyod what we have traditioally defied as elderly. The existece of similar differeces at other stages i the life cycle is clearly established: youg childre are differet from adolescets, who are differet from adults. As with ay biologic pheomeo, the age of oset varies. Sex differeces, possibly related to rates of agig, are also importat. Results from studies that iclude both youger elderly ad the very old are probably iflueced by these age ad sex effects ad will likely show the effects associated with the predomiat age-sex group. Effect estimates from such studies could also be iflueced ad most likely would be weakeed by these age ad sex iteractios. Most studies of the elderly reported to date are based o populatios with mea ages earer to 70 tha 80 years, so they may ot show effects cosistet with aalyses limited to the very old. The fidig, isolated to me, that a drop i DBP associated with use of atihypertesive medicatio was associated with icreased mortality suggests that cautio is warrated i the use of atihypertesive treatmet i very old me. This study used observatioal data; further study of these associatios usig cliical trial data from atihypertesive studies i me, ad perhaps wome, aged 75 years ad older is idicated. These results suggest that, i treatig ISH i me aged 75 years ad older, drugs ad doses that reduce SBP while preservig DBP may be associated with better survival tha treatmets that reduce both compoets. These fidigs also raise the possibility that treatmet of diastolic hypertesio i me 75 years or older should be reserved for those with substatial, ot moderate, elevatios of DBP. Ackowledgmet Supported by grat 1RO1 HL-44689 from the Natioal Heart, Lug, ad Blood Istitute, Natioal Istitutes of Health, Bethesda, Md. Refereces 1. US Bureau of the Cesus. Projectios of the Populatio of the Uited States, by Age, Sex, ad Race: 1988 to 2080. Curret Populatio Reports, Series P-25, No. 1018. Washigto, DC: US Govermet Pritig Office; 1989:40-85. 2. Lager RD, Gaiats TG, Barrett-Coor E. Paradoxical survival with higher blood pressures i older me. Br Med J. 1989;298: 1356-1357.

Loger et al Blood Pressure ad Survival After Age 75 559 3. Mattila K, Haavisto M, Rajala S, Heikihiemo R. Blood pressure ad five year survival i the very old. Br Med J. 1988;296:887-889. 4. Staesse J, Fagard R, Va Hoof R, Amery A. Atihypertesive drug treatmet i elderly hypertesive subjects: evidece of protectio. J Cardiovasc Pharmacol 1988;12(suppl 8):S33-S38. 5. Taylor JO, Coroi-Hutley J, Curb JD, Mato KG, Ostfeld AM, Scherr P, Wallace RB. Blood pressure ad mortality risk i the elderly. Am J Epidemiol 1991;134:489-501. 6. Stroke Prevetio i Atrial Fibrillatio Study Group. Prelimiary report of the Stroke Prevetio i AtriaJ Fibrillatio Study. N Egl J Med. 1990-^22:863-868. 7. Lager RD, Gaiats TG, Barrett-Coor E. Factors associated with paradoxical survival at higher blood pressures i the very old. Am J Epidemiol 1991;134:29-38. 8. Hypertesio Detectio ad Follow-up Program Cooperative Group. The Hypertesio Detectio ad Follow-up Program. Prev Med. 1976^:207-215. 9. Ettiger WH, Wahl PW, Kuller LH, Bush TL, Tracy RP, Maolio TA, Borhai NO, Wog ND, O'Leary DH. Lipoprotei lipids i older people: results from the Cardiovascular Health Study. Circulatio. 1992;86:858-869. 10. SHEP Cooperative Research Group. Prevetio of stroke by atihypertesive drug treatmet i older persos with isolated systolic hypertesio: fial report of the Systolic Hypertesio i the Elderly Program (SHEP). JAMA 1991;265:3255-3264. 11. Amery A, Birkehager W, Brixko R, Bulpitt C, Clemet D, Deruyttere M, De Schaepdryver A, Dollery C, Fagard R, Forette F, Forte J, Hamdy R, Hery JF, Joosses JV, Leoetti G, Lud- Johase P, O'Malley K, Petrie JC, Strasser T, Tuomilehto J, Williams B. Efficacy of atihypertesive drug treatmet accordig to age, sex, blood pressure, ad previous cardiovascular disease i patiets over the age of 60. Lacet 1986;2:589-592. 12. D'Agostio RB, Belager AL, Kael WB, Cruickshak JM. Relatio of low diastolic blood pressure to coroary heart disease death i presece of myocardial ifarctio: the Framigham study. BrMedJ. 1991^03:385-388. 13. Lakatta EG. Chages i cardiovascular fuctio with agig. Eur Heart J. 199O;ll(suppl Q:22-29. 14. Weiberger M. Hypertesio i the elderly. Hasp Prac (Off Ed). 1992;27:67-80. 15. Bulpitt CJ. Is systolic pressure more importat tha diastolic pressure? / Hum Hypertes. 1990;4:471-476.

Blood pressure chage ad survival after age 75. R D Lager, M H Criqui, E L Barrett-Coor, M R Klauber ad T G Gaiats Hypertesio. 1993;22:551-559 doi: 10.1161/01.HYP.22.4.551 Hypertesio is published by the America Heart Associatio, 7272 Greeville Aveue, Dallas, TX 75231 Copyright 1993 America Heart Associatio, Ic. All rights reserved. Prit ISSN: 0194-911X. Olie ISSN: 1524-4563 The olie versio of this article, alog with updated iformatio ad services, is located o the World Wide Web at: http://hyper.ahajourals.org/cotet/22/4/551 Hypertesio Permissios: Requests for permissios to reproduce figures, tables, or portios of articles origially published i ca be obtaied via RightsLik, a service of the Copyright Clearace Ceter, ot the Editorial Office. Oce the olie versio of the published article for which permissio is beig requested is located, click Request Permissios i the middle colum of the Web page uder Services. Further iformatio about this process is available i the Permissios ad Rights Questio ad Aswer documet. Reprits: Iformatio about reprits ca be foud olie at: http://www.lww.com/reprits Subscriptios: Iformatio about subscribig to Hypertesio is olie at: http://hyper.ahajourals.org//subscriptios/