1. OPTIMAL BLOOD PRESSURE LEVELS IN ELDERLY PERSONS IN THE REASONS FOR GEOGRAPHIC AND RACIAL DIFFERENCES IN STROKE (REGARDS) COHORT STUDY Maciej Banach*, Samantha Bromfield, George Howard, Virginia J. Howard, Alberto Zanchetti, Wilbert S. Aronow, Ali Ahmed, Monika M. Safford, Paul Muntner *Prof. Maciej Banach, MD, PhD, FESC, FAHA, FNLA Head, Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Zeromskiego 113; 90-549 Lodz, Poland

2. REGARDS Study The REasons for Geographic and Racial Differences in Stroke (REGARDS) project is a national study focusing on learning more about the factors that increase a person's risk of having a stroke. REGARDS is an observational study of risk factors for stroke in adults 45 years or older. 30,239 participants were recruited between January 2003 and October 2007. http://www.regardsstudy.org/

3. REGARDS Study The study was designed to oversample blacks and individuals living in the “stroke belt” and “stroke buckle” regions of the United States. The “stroke buckle” was defined as the coastal plain region of North Carolina, South Carolina, and Georgia and the “stroke belt” as the remainder of North Carolina, South Carolina, and Georgia as well as Alabama, Mississippi, Tennessee, Arkansas and Louisiana. http://www.regardsstudy.org/NC SC GA AL MS TN AR LA

4. Optimal BP level in the elderly What guidelines say? ACCF/AHA 2011 guidelines suggest a target of <140/90 mmHg in persons aged 65-79 years and an systolic BP (SBP) of 140-145 mmHg, if tolerated, in persons aged 80 years and older is reasonable. ESH/ESC 2013 guidelines suggest that in the elderly hypertensives both less and over 80 years old with SBP ≥160 mmHg it is recommended to reduce SBP to between 150 and 140 mmHg. However, in fit patients <80 years old SBP values <140 mmHg may be considered, whereas in the fragile elderly population SBP goals should be adapted to individual tolerability. Aronow WS, et al. Circulation 2011;123:2434-506. Mancia G, et al. J Hypertens 2013;31:1281-1357.

5. Optimal BP level in the elderly The issue of increasing of the elderly population 1 billion persons worldwide have HTN and about 7 million die of HTN each year. HTN is the leading cause of mortality and the third cause of disability. About 54% of strokes and 47% of CHD are attributable to high BP; HTN is present in approximately 69% of patients with a first MI, in approximately 77% of patients with a first stroke, in approximately 74% of patients with CHF and in 60% of patients with PAD. In Europe the average life expectancy at birth has risen from 65.6 years in 1950-1955 to 75.1 years in 2005-2010, and it is still expected to rise to 85.3 years for women and 80.0 years for men. Over 34 million Americans are currently ≥65 years of age and this number is expected to reach 75 million by 2040, representing more than >20% of the US population. Individuals >85 years of age are the largest growing subset in the US. Lozano R, et al. Lancet 2012;380:2095-128. Go AS, et al. Circulation 2013;127:e6-e245. Banach M, Aronow WS. J Hum Hypertens 2012;26:641-3. Leis M, Gijsbers G. European Foresight Platform, 2011.

6. Although definite evidence about the optimal BP to be targeted by antihypertensive treatment in the elderly can only be established by an appropriate controlled randomized trial, in absence of these data our aim was to investigate the BP associated with the lowest CV risk in elderly persons on the basis of data from a national observational cohort study in the United States, the REasons for Geographic And Racial Differences in Stroke (REGARDS). Optimal BP level in the elderly AIM of the study

7. Optimal BP level in the elderly METHODS - Study Participants *Participants with a history of CHD (n=3,310) were excluded from analyses of incident CHD, and with a history of stroke (n=1,333) and CVD (n=4,161) were excluded from analyses of these outcomes. Between Jan. 1 st 2003 and Oct. 31 st 2007, 30,239 participants were enrolled The analysis was limited to participants 55 years of age and older (n=26,396). We excluded : -participants without valid SBP/DBP measurements at baseline (n=78) -with missing follow-up data (n=414) -participants who were not taking antihypertensive medications at baseline (n=11,956) Finally 13,948 participants were included to the study *

8. Optimal BP level in the elderly METHODS - Study Outcomes REGARDS participants were contacted by telephone every 6 months following baseline to assess stroke and CHD events and all-cause mortality. Medical records were retrieved for suspected stroke and CHD-related hospitalizations and deaths. We studied 4 outcomes in the current analysis: CVD (the first occurrence of a CHD or stroke event), CHD (nonfatal MI or CHD death), stroke and all-cause mortality. Median follow-up for CVD and CHD was 4.5 years (maximum 7 years), for stroke was 5.7 years (maximum 8.5 years) and for all-cause mortality was 6.0 years (maximum 9.1 years).

9. Optimal BP level in the elderly Baseline characteristics of the population by age Age (years) 55-64 (n = 4181) 65-74 (n = 3767) ≥ 75 (n = 1839) p-value Age, y 59.7 (2.8)69.0 (2.8)79.3 (3.7) Men, % 38.039.336.90.580 Black, % 56.260.045.4<0.001 Region of Residence Stroke belt, % 36.934.031.8 <0.001 Stroke buckle, % 21.921.118.9 Non-belt, % 63.166.168.2 Less than a high school education, % 10.815.420.9<0.001 Household Income < $20,000, % 19.124.030.4<0.001 Current smoker, % 16.09.75.2<0.001 Diabetes Mellitus, % 28.928.424.70.005 Isolated Systolic Hypertension, % 14.621.025.7<0.001 HDL-cholesterol (mg/dL), mean (sd) 51.2 (15.5)52.2 (16.4)53.9 (16.7)<0.001 LDL-cholesterol (mg/dL), mean (sd) 114.7 (34.0)110.2 (33.7)109.9 (31.9)<0.001 Total cholesterol (mg/dL), mean (sd) 193.2 (37.8)189.3 (39.2)188.7 (37.8)<0.001 Atrial Fibrillation, % 7.67.411.0<0.001 Dyslipidemia, % 59.361.156.60.216 Follow-up** Cardiovascular disease events 154 (3.6%)217 (5.7%)159 (8.5%)<0.001 Coronary heart disease events 112 (2.4%)145 (3.5%)106 (5.1%)<0.001 Stroke 101 (1.9%)188 (3.8%)136 (5.2%)<0.001 All-cause mortality 460 (8.2%)775 (14.1%)860 (28.4%)<0.001

10. Optimal BP level in the elderly Number of events per outcome by level of SBP and age Systolic blood pressure category in mmHg Age 55 to 64 years<120120 – 129130 – 139140 – 149≥150 CVD 2746312129 CHD 1829251723 Stroke 1531231814 All-cause mortality 861129484 Systolic blood pressure category in mmHg Age 65 to 74 years<120120 – 129130 – 139140 – 149≥150 CVD 33 48553546 CHD 24 31302337 Stroke 33 39553328 All-cause mortality 136 169183132155 Systolic blood pressure category in mmHg Age ≥ 75 years<120120 – 129130 – 139140 – 149≥150 CVD 2732272349 CHD 1615201837 Stroke 2032 2131 All-cause mortality 153202179164162

11. Optimal BP level in the elderly CVD incidence rates and hazard ratios by SBP and age Systolic blood pressure category in mmHg Age 55 to 64 years <120 (n = 949) 120-129 (n = 1189) 130-139 (n = 1006) 140-149 (n = 592) ≥150 (n = 445) p-linearp-quadratic Incidence† (95% CI) Model 3* 6.4 (4.2-9.9) 8.8 (6.5-12.0) 5.7 (3.9-8.3) 6.3 (3.9-10.1) 10.1 (6.3-16.1) 0.4740.236 Hazard ratio (95% CI) Model 31 (ref) 1.37 (0.82-2.28) 0.88 (0.50-1.57) 0.98 (0.51-1.88) 1.56 (0.79-3.09) 0.4810.237 Systolic blood pressure category in mmHg Age 65 to 74 years <120 (n = 772) 120-129 (n =1018) 130-139 (n = 923) 140-149 (n = 602) ≥150 (n = 452) p-linearp-quadratic Incidence† (95% CI) Model 3 8.7 (6.0-12.6) 9.9 (7.3-13.4) 11.7 (8.8-15.6) 12.5 (8.8-17.8) 20.2 (14.3-28.6) 0.0010.452 Hazard ratio (95% CI) Model 31 (ref) 1.14 (0.72-1.80) 1.34 (0.85-2.14) 1.44 (0.86-2.41) 2.33 (1.37-3.97) 0.0010.443 Systolic blood pressure category in mmHg Age ≥ 75 years <120 (n = 343) 120-129 (n = 479) 130-139 (n = 448) 140-149 (n = 278) ≥150 (n = 291) p-linearp-quadratic Incidence† (95% CI) Model 3 16.9 (11.1-25.7) 13.4 (9.2-19.7) 11.6 (7.6-17.7) 17.8 (11.5-27.5) 36.7 (26.6-50.8) <0.0010.002 Hazard ratio (95% CI) Model 31 (ref) 0.80 (0.46-1.38) 0.69 (0.39-1.24) 1.06 (0.58-1.93) 2.18 (1.27-3.76) <0.0010.002 † Incidence per 1,000 person-years. * Model 3 is adjusted for age, race, gender, region of residence, income and education, as well as for dyslipidemia, diabetes, current smoking, atrial fibrillation and diastolic blood pressure.

12. Optimal BP level in the elderly CHD incidence rates and hazard ratios by SBP and age Systolic blood pressure category in mmHg Age 55 to 64 years < 120 (n=995) 120 – 129 (n=1265) 130 – 139 (n=1083) 140 – 149 (n=644) ≥ 150 (n=496) p-linearp-quadratic Incidence† (95% CI) Model 3 3.4 (2.0-5.9) 4.3 (2.8-6.5) 4.4 (2.9-6.6) 5.1 (3.1-8.5) 8.1 (4.9-13.6) 0.0280.536 Hazard ratio (95% CI) Model 31 (ref) 1.26 (0.65-2.43) 1.27 (0.64-2.51) 1.49 (0.70-3.19) 2.38 (1.08-5.26) 0.0280.533 Systolic blood pressure category in mmHg Age 65 to 74 years < 120 (n=837) 120 – 129 (n=1109) 130 – 139 (n=994) 140 – 149 (n=652) ≥ 150 (n=497) p-linearp-quadratic Incidence† (95% CI) Model 3 4.9 (3.1-7.7) 5.6 (3.8-8.1) 5.5 (3.7-8.1) 6.7 (4.3-10.5) 13.5 (9.1-20.0) 0.0280.091 Hazard ratio (95% CI) Model 31 (ref) 1.14 (0.66-1.98) 1.11 (0.62-1.97) 1.37 (0.74-2.54) 2.74 (1.50-5.04) 0.0010.090 Systolic blood pressure category in mmHg Age ≥ 75 years < 120 (n=380) 120 – 129 (n=544) 130 – 139 (n=499) 140 – 149 (n=318) ≥ 150 (n=325) p-linearp-quadratic Incidence† (95% CI) Model 3 8.1 (4.7-13.9) 4.9 (2.8-8.6) 8.1 (5.1-12.9) 13.7 (8.5-22.0) 23.2 (15.8-34.2) <0.0010.095 Hazard ratio (95% CI) Model 31 (ref) 0.60 (0.28-1.28) 0.99 (0.50-1.99) 1.69 (0.82-3.45) 2.86 (1.47-5.58) <0.0010.095 † Incidence per 1,000 person-years. * Model 3 is adjusted for age, race, gender, region of residence, income and education, as well as for dyslipidemia, diabetes, current smoking, atrial fibrillation and diastolic blood pressure.

13. Optimal BP level in the elderly Stroke incidence rates and hazard ratios by SBP and age Systolic blood pressure category in mmHg Age 55 to 64 years < 120 (n=1154) 120 – 129 (n=1435) 130 – 139 (n=1210) 140 – 149 (n=723) ≥ 150 (n=553) p-linearp-quadratic Incidence† (95% CI) Model 3 2.4 (1.4-4.3) 3.5 (2.4-5.2) 2.8 (1.8-4.3) 3.6 (2.1-6.0) 3.2 (1.7-6.1) 0.6590.607 Hazard ratio (95% CI) Model 31 (ref) 1.44 (0.74-2.80) 1.15 (0.56-2.37) 1.48 (0.67-3.25) 1.33 (0.53-3.32) 0.6560.605 Systolic blood pressure category in mmHg Age 65 to 74 years < 120 (n=1009) 120 – 129 (n=1298) 130 – 139 (n=1219) 140 – 149 (n=762) ≥ 150 (n=624) p-linearp-quadratic Incidence† (95% CI) Model 3 5.7 (3.9-8.3) 5.3 (3.8-7.3) 7.3 (5.5-9.7) 7.5 (5.2-10.8) 6.8 (4.4-10.5) 0.2910.499 Hazard ratio (95% CI) Model 31 (ref) 0.92 (0.57-1.49) 1.28 (0.80-2.04) 1.32 (0.78-2.25) 1.20 (0.66-2.18) 0.2830.492 Systolic blood pressure category in mmHg Age ≥ 75 years < 120 (n=500) 120 – 129 (n=663) 130 – 139 (n=645) 140 – 149 (n=401) ≥ 150 (n=419) p-linearp-quadratic Incidence† (95% CI) Model 3 8.7 (5.4-14.0) 8.4 (5.7-12.4) 8.5 (5.8-12.5) 9.1 (5.7-14.6) 13.6 (9.2-20.2) 0.1020.272 Hazard ratio (95% CI) Model 31 (ref) 0.99 (0.54-1.79) 1.00 (0.54-1.84) 1.07 (0.54-2.11) 1.61 (0.84-3.07) 0.091#0.282 † Incidence per 1,000 person-years. * Model 3 is adjusted for age, race, gender, region of residence, income and education, as well as for dyslipidemia, diabetes, current smoking, atrial fibrillation and diastolic blood pressure. # The significant relation for p = 0.021 was observed for Model 1 and 2.

14. Optimal BP level in the elderly All-cause mortality rates and hazard ratios by SBP and age Systolic blood pressure category in mmHg Age 55 to 64 years < 120 (n=1223) 120 – 129 (n=1544) 130 – 139 (n=1325) 140 – 149 (n=795) ≥ 150 (n=626) p-linearp-quadratic Incidence† (95% CI) Model 3 9.3 (7.2-12.0) 10.0 (8.1-12.3) 9.4 (7.5-11.8) 14.0 (11.0-17.8) 16.4 (12.5-21.4) <0.0010.283 Hazard ratio (95% CI) Model 31 (ref) 1.07 (0.79-1.47) 1.02 (0.73-1.42) 1.50 (1.06-2.14) 1.77 (1.20-2.62) 0.0010.272 Systolic blood pressure category in mmHg Age 65 to 74 years < 120 (n=1118) 120 – 129 (n=1437) 130 – 139 (n=1336) 140 – 149 (n=844) ≥ 150 (n=703) p-linearp-quadratic Incidence† (95% CI) Model 3 16.5 (13.6-21.0) 17.4 (14.8-20.6) 19.2 (16.4-22.5) 22.3 (18.6-26.9) 27.6 (22.7-33.4) <0.0010.433 Hazard ratio (95% CI) Model 31 (ref) 1.06 (0.83-1.34) 1.16 (0.91-1.48) 1.35 (1.03-1.75) 1.67 (1.27-2.21) <0.0010.413 Systolic blood pressure category in mmHg Age ≥ 75 years < 120 (n=568) 120 – 129 (n=764) 130 – 139 (n=724) 140 – 149 (n=459) ≥ 150 (n=482) p-linearp-quadratic Incidence† (95% CI) Model 3 49.4 (41.2-59.2) 43.5 (37.2-50.7) 40.1 (34.2-47.0) 59.8 (50.5-70.8) 51.0 (42.7-60.9) 0.2190.336 Hazard ratio (95% CI) Model 31 (ref) 0.86 (0.68-1.08) 0.78 (0.62-0.99) 1.18 (0.91-1.51) 1.00 (0.77-1.29) 0.3190.245 † Incidence per 1,000 person-years. * Model 3 is adjusted for age, race, gender, region of residence, income and education, as well as for dyslipidemia, diabetes, current smoking, atrial fibrillation and diastolic blood pressure.

15. Optimal BP level in the elderly Study limitations  BP was measured 2 times on a single occasion which may have led to exposure misclassification for some study participants;  The study is observational and the causality of the optimal BP for reducing CVD outcomes cannot be determined;  Relatively low number of stroke and CHD cases in some of the subgroups;  The REGARDS study was done in the stroke belt (31.8-36.9% of included subjects depending on the age group) in a population with a high African-American percentage (45.4-60% of included subjects depending on the age group). However these variables were adjusted for the final results, and the group of included patients was large enough (almost 14,000) in order to generate a hypothesis on optimal SBP levels in this group of patients.

16. Optimal BP level in the elderly Conclusions  The results of REGARDS cohort study generate a hypothesis that for all patients >55 years the recommended level of SBP should be <140 mmHg with optimal values possibly between 120-139 mmHg.  Intensive hypertension treatment (BP <120 mmHg) should be a matter of further investigations.  Large, well-designed, interventional randomized controlled trials are required to provide definitive insights into the optimal BP levels in elderly persons.  All future trials addressing the optimal SBP goal should also take into account an individual’s frailty status.