Antonio Coca, MD, PhD, FRCP, FESC What Target Blood Pressure Levels are the Optimal for Cardiovascular Prevention? Antonio Coca, MD, PhD, FRCP, FESC Hypertension and Vascular Risk Unit. Department of Internal Medicine . Hospital Clínic (IDIBAPS) University of Barcelona, Spain Conflict of interest concerning this presentation: None Congress of the Romanian Society of Hypertension Bucharest, September 17th, 2016 © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona

High Risk Hypertensive Patients Hypertension in the elderly Hypertension in type 2 Diabetes Hypertension in patients with CVRF and silent TOD Hypertension after Stroke Hypertension after Coronary Artery Disease Hypertension in Heart Failure Hypertension in Chronic Kidney Disease 2007 ESH/ESC Guidelines. J Hypertens 2007; 25: 1105–1187 2003 ESH/ESC Guidelines. J Hypertens 2003; 21: 1011-1053 © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona

Blood Pressure Changes in Trials on Elderly Hypertensive Patients 200 190 186 Benefit Partial No 180 180 172 170 170 165 Baseline and achieved SBP (mmHg) 167 161 160 159 160 162 156 150 148 147 150 151 151 140 143 145 144 140 138 130 120 110 100 EW SHEP MRC S. Eur S. Ch SCOPE JATOS CW STOP HYVET © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona Zanchetti et al. J Hypertens 2009; 27: 923-934

Risk of Cardiovascular Events According to the DBP Achieved in the SHEP Study 10 Relative Risk 9 95% Confidence Interval 8 7 P < 0.001 for trend Relative Risk 6 5 4 3 2 1 80 75 70 65 60 55 50 45 40 35 30 25 DBP (mmHg) © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona Somes et al. Arch Intern Med 1999; 159: 2004-2009

Reduction in BP and Stroke Risk in Treated Hypertensive Patients: the Rotterdam Study DBP (mmHg) SBP (mmHg) 4 4 2 Relative Risk 2 1 1 0.5 0.5 0.25 <65 65-74 75-84 >84 <130 130-149 150-169 >169 © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona Vokó et al. Hypertension 1999; 34: 1181-1185

High Risk Hypertensive Patients Hypertension in the elderly Hypertension in type 2 Diabetes Hypertension in patients with CVRF and silent TOD Hypertension after Stroke Hypertension after Coronary Artery Disease Hypertension in Heart Failure Hypertension in Chronic Kidney Disease 2007 ESH/ESC Guidelines. J Hypertens 2007; 25: 1105–1187 2003 ESH/ESC Guidelines. J Hypertens 2003; 21: 1011-1053 © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona

Blood Pressure Changes in Trials on Diabetic Hypertensive Patients 170 170 50 162 160 160 40 155 40 154 153 34 34 Baseline and achieved SBP (mmHg) 150 150 31 148 30 % CV event reduction 25 145 145 144 143 140 140 140 138 20 137 139 134 130 130 132 10 8 128 120 120 S. Eur DM SHEP DM UK PDS HOT DM HOPE ADV ABCD HT ABCD NT © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona Zanchetti et al. J Hypertens 2009; 27: 923-934

Blood Pressure Achieved and Cardiovascular Prevention in ACCORD Study Primary Outcome Nonfatal MI, Nonfatal Stroke or CVD Death Secondary outcome Total Stroke Patients with Events (%) 20 15 10 5 HR = 0.59 95% CI (0.39-0.89) 8 7 6 4 3 2 1 41% Intensive (final SBP 119 mmHg) Standard (final SBP 133 mmHg) 20 HR = 0.89 95% CI (0.73-1.07) 11% 15 10 Patients with Events (%) Intensive (final SBP 119 mmHg) Standard (final SBP 133 mmHg) 5 1 2 3 4 5 6 7 8 Years Post-Randomization Years Post-Randomization © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona N Eng J Med 2010; March 14 on-line

High Risk Hypertensive Patients Hypertension in the elderly Hypertension in type 2 Diabetes Hypertension in patients with CVRF and silent TOD Hypertension after Stroke Hypertension after Coronary Artery Disease Hypertension in Heart Failure Hypertension in Chronic Kidney Disease 2007 ESH/ESC Guidelines. J Hypertens 2007; 25: 1105–1187 2003 ESH/ESC Guidelines. J Hypertens 2003; 21: 1011-1053 © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona

Blood Pressure Targets and Stroke Protection in the ONTARGET Study Incidence of Stroke according to the % of in-treatment visits in which BP was found to be reduced to < 130/80 mmHg 3 (n= 16743) 2.4 Visits with BP<130/80 mmHg <25% 25-49% 50-74% ≥75% 2.2 2 Incidence (%) 1.2 1.1 Include patients with baseline SBP ≥ 130 and ≥ 7 in- treatment visits before the endpoint 1 9141 4288 2282 1032 145 133 125 116 82 76 72 68 © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona Mancia et al. Circulation 2011; 124: 1727-1736

Blood Pressure Targets and Kidney Protection in the ONTARGET Study Incidence of renal events according to the % of visits in which BP was reduced to < 140/90 or < 130/80 mmHg ESRD Doubling of SCr 1.5 2 Visits with BP at target <25% 25-49% 50-74% ≥75% 1.8 Visits with BP at target <25% 25-49% 50-74% ≥75% 1.2 1.5 1.5 1.4 1 0.8 0.8 1.0 % % 1 1.0 1.0 0.9 0.5 0.6 0.4 0.4 0.3 0.3 0.5 0.1 < 140/90 mmHg < 130/80 mmHg < 140/90 mmHg < 130/80 mmHg © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona Mancia et al. Circulation 2011; 124: 1727-1736

Blood Pressure Targets and Protection for Myocardial Infarction in the ONTARGET Study Incidence of MI according to the % of in-treatment visits in which BP was found to be reduced to < 130/80 mmHg 1 2 3 (n= 16,711) 2.2 2.3 2.1 1.7 Visits with BP<130/80 mmHg <25% 25-49% 50-74% ≥75% Include patients with baseline SBP ≥ 130 and ≥ 7 in- treatment visits before the endpoint Incidence (%) n 9183 4258 2245 1025 SBP 145 133 125 116 DBP 82 76 72 68 © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona Mancia et al. Circulation 2011; 124: 1727-1736

High Risk Hypertensive Patients Hypertension in the elderly Hypertension in type 2 Diabetes Hypertension in patients with CVRF and silent TOD Hypertension after Stroke Hypertension after Coronary Artery Disease Hypertension in Heart Failure Hypertension in Chronic Kidney Disease © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona Reappraisal ESH/ESC Guidelines. J Hypertens 2009; 27: 2121-2157

Blood Pressure Lowering and Secondary Prevention of Stroke PROGRESS Study Stroke Prevention Treat (n= 2051) Placebo (n= 3054) Favours treat Favours placebo RR (95% CI) reduction Combination Monotherapy Hypertensive Non-Hypertensive Total 150 157 163 144 307 255 165 235 185 420 43% (30 - 54) 5% (-19 - 23) 32% (17 - 44) 27% (8 - 42) 28% (17 - 38) BP reduction vs placebo: Monotherapy: 4.9/2.8 mmHg Combination: 12.3/5.0 mmHg 0.5 1.0 2.0 © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona PROGRESS. Lancet 2001; 358: 1033-1041

Long-Term Blood Pressure Lowering and Secondary Prevention of Stroke Trials of Antihypertensive Treatment in Patients With Previous Stroke or TIA 160 160 50 43% 40 150 150 149 29% Achieved SBP (mmHg) 28% 143 30 % Stroke reduction 144 140 140 140 141 138 20 136 134 132 130 130 130 10 5% 5% 120 PATS All Comb Mono PROF PROGRESS © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona Zanchetti et al. J Hypertens 2009; 27: 923-934

Different BP Targets for Secondary Prevention of Stroke? The results of the PROGRESS trial clearly show the benefits of lowering BP in patients with previous cerebrovascular events However, these results do not support the previous ESH/ESC 2007 recommendation of lowering SBP below 130 mmHg to prevent stroke recurrences © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona Reappraisal ESH/ESC Guidelines. J Hypertens 2009; 27: 2121-2157

Blood Pressure Lowering in Secondary Stroke Prevention: the SPS3 Study The Secondary Prevention of Small Subcortical Strokes (SPS3) trial 3020 patients with lacunar (small-vessel disease) strokes 495 (16%) aged ≥ 75 years at baseline. Mean follow up 3.6 years Mean baseline SBP: 144 mmHg Randomized (open label) to 2 different target levels of SBP control: - SBP <150 versus <130 mm Hg Primary outcome: recurrent stroke Achieved average SBP at 12 months (11 mmHg difference): - 138 mmHg vs 127 mmHg in the lower-target group © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona White et al. J Am Geristr Soc 2015; 63: 722-729

Blood Pressure Lowering in Secondary Stroke Prevention: the SPS3 Study HR= 0.81; 95% CI [0.64–1.03] © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona White et al. J Am Geristr Soc 2015; 63: 722-729

Which are the Optimal Blood Pressure Targets for Secondary Stroke Prevention? The ESH/CHL – SHOT trial (the Stroke in Hypertension Optimal Treatment trial) promoted by the ESH and the CHL has been designed to address this issue Three different SBP targets will be explored in relation to stroke recurrences in patients with previous stroke or TIA: < 145 to 135 mmHg < 135 to 125 mmHg < 125 mmHg © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona Zanchetti A, et al. J Hypertens 2014; 32:1888-1889

Blood Pressure Lowering and Secondary Prevention of Coronary Artery Disease Trials of Antihypertensive Treatment in Patients With CAD 150 140 140 138 136 Achieved SBP (mmHg) 136 135 133 132 130 130 130 130 130 129 128 124 124 122 120 130 110 HOPE ACT CAM PEA PREV EU AM EN TR © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona Zanchetti et al. J Hypertens 2009; 27: 923-934

What is the Optimal SBP in Patients after Acute Coronary Syndromes? Incidence and adjusted risk of primary outcome as a function of average follow-up SBP categories in the PROVE IT-TIMI 22 trial 60 6 Adjusted Hazard Ratio (baseline covariates, treatment effect, hsCRP, in-treat LDL-C) Primary outcome: n= 1000 (24%) 50 5 40 4 Nadir 136 mmHg Incidence of Primary Outcome (%) 30 Adjusted Hazard Ratio 3 20 2 10 1 >100 to 110 >110 to 120 >120 to 130 >130 to 140 >140 to 150 >150 to 160 <100 > 160 Systolic Blood Pressure, mmHg © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona Bangalore et al. Circulation 2011; 122: 2142-2151

What is the Optimal SBP in Patients after Acute Coronary Syndromes? Incidence and adjusted risk of all-cause mortality as a function of average follow-up SBP categories in the PROVE IT-TIMI 22 trial 15 14 Adjusted Hazard Ratio (baseline covariates, treatment effect, hsCRP, in-treat LDL-C) Total mortality: 119 (2.9%) 12 10 10 8 Nadir 132 mmHg Incidence of All-Cause Mortality (%) Adjusted Hazard Ratio 6 4 5 2 -2 >100 to 110 >110 to 120 >120 to 130 >130 to 140 >140 to 150 >150 to 160 <100 > 160 Systolic Blood Pressure, mmHg © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona Bangalore et al. Circulation 2011; 122: 2142-2151

Blood Pressure Lowering and Cardiovascular Prevention © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona Thomopoulos et al. J Hypertens 2016; 34: 613–622

2013 ESH/ESC Guidelines Recommendations Antihypertensive Treatment Goals BP < 140/90 mmHg Class I Level B In low-moderate risk hypertensives In hypertensives with previous Stroke or TIA In hypertensives with Coronary Artery Disease (CAD) In hypertensives with Chronic Kidney Disease (CKD) Class IIa BP < 140/85 mmHg Class I Level A In hypertensives with Diabetes BP < 150/90 mmHg Class I Level A In hypertensives ≥ 65 years 2013 ESH/ESC Guidelines. J Hypertens 2013; 31: 1281–1357 2013 ESH/ESC Guidelines. Eur Heart J 2013; 34: 2159-2219 © A. Coca Hospital Clínic. IDIBAPS Universidad Barcelona

Optimal Blood Pressure Targets in the SPRINT Study < 140 mmHg (136.2 mmHg) < 120 mmHg (121.2 mmHg) © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona SPRINT Research Group. N Eng J Med 2015; 373: 2103-2116

Optimal Blood Pressure Targets in the SPRINT Study © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona SPRINT Research Group. N Eng J Med 2015; 373: 2103-2116

Optimal Blood Pressure Targets in the SPRINT Study Primary Outcome Total Mortality © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona SPRINT Research Group. N Eng J Med 2015; 373: 2103-2116

Primary Outcome in Different Subgroups © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona SPRINT Research Group. N Eng J Med 2015; 373: 2103-2116

Optimal Blood Pressure Targets in the SPRINT Study Stroke Outcomes in Adults Aged  75 years © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona SPRINT Research Group. JAMA 2016; 315: 2673-2682

Summary and Conclusions The J-curve phenomenon between BP and CV events is a reality for CV events, but the shape of the curve and BP nadir are different for stroke, CAD and CKD Blood pressure may be safely reduced to very low limits which differ in different clinical situations, in primary or secondary prevention, and even in different patients with similar CV events Robust evidence is lacking, and the lowest safe BP values to be achieved by treatment in patients with stroke or CAD must be investigated in future clinical trials © A. Coca Hospital Clínico. IDIBAPS Universidad Barcelona