Blood Pressure Targets: Where are We Now?

Blood Pressure Targets: Where are We Now? Diana Cao, PharmD, BCPS-AQ Cardiology Assistant Professor Department of Clinical & Administrative Sciences California Northstate University College of Pharmacy

Disclosure I have no actual or potential conflict of interest in relation to this program.

Learning Objectives 1. Discuss guideline recommendations regarding blood pressure goals 2. Describe results from recent hypertension trials 3. Select appropriate blood pressure goals for patients with hypertension

Introduction Hypertension (HTN) is a major risk factor for cardiovascular (CV) diseases About one in three US adults has HTN $48.6 billion direct and indirect cost annually Increasing mortality from 2003-2013 Approximately half hypertensives are under control Mozaffarian D, et. al. Heart disease and stroke statistics 2016. Circulation. 2016;133(4):e38-60. CDC. High blood pressure fact sheet. Retrieved from http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/docs/fs_bloodpressure.pdf

Introduction Mozaffarian D, et. al. Heart disease and stroke statistics 2016. Circulation. 2016 Jan 16;133(4):e38-60.

Guideline Recommendations JNC 8 (2014) ESH/ESC (2013) ASH/ISH (2014) General Population < 140/90 mm Hg < 140/90 mm Hg < 140/90 mm Hg Elderly Chronic Kidney Disease Older than 60 years of age < 150/90 mm Hg Younger than 80 years of age SBP 140-150 mm Hg for most, may consider < 140 mm Hg in those who are fit DBP < 90 mm Hg Older than 80 years of age SBP 140-150 mm Hg and DBP < 90 if in good physical and mental conditions < 140/90 mm Hg < 140/90 mm Hg (SBP < 130 mm Hg when overt proteinuria is present) Older than 80 years of age < 150/90 mm Hg unless chronic kidney disease or diabetes < 140/90 mm Hg Diabetes Mellitus < 140/90 mm Hg < 140/85 mm Hg < 140/90 mm Hg James PA, et. al. 2014 Evidence-based guideline for the management of high blood pressure in adults. JAMA. 2014;311(5):507-520. Weber MA, et. al. Clinical practice guideline for the management of hypertension in the community. J Clin Hypertens. 2014;16(1):14-26. Mancia G, et. al. 2013 ESH/ESC Practice guidelines for the management of arterial hypertension. Eur Heart J. 2013;34(28):2159-219.

Recent Trials

SPRINT Systolic Blood Pressure Intervention Trial (SPRINT) SBP between 130-180 mm Hg, age 50 years or greater, increased cardiovascular risk but without diabetes or stroke (N=9361) SBP target of < 120 mm Hg (N=4678) SBP target of < 140 mm Hg (N=4683) All major classes of antihypertensives used Primary outcome composite of myocardial infarction (MI), acute coronary syndrome (ACS) not resulting in myocardial infarction, stroke, acute decompensated heart failure, or death from CV causes Median follow up 3.26 years Wright JT, et. al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-16.

SPRINT Mean systolic blood pressure (SBP) at one year 139.7 121.4 mm Hg in intensive-treatment group vs. 139.7 136.2 mm Hg in standard-treatment group 1.65% per year vs. 2.19% per year 1.03% per year vs. 1.40% per year Wright JT, et. al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-16.

SPRINT No difference in the overall rates of serious adverse events (38.3% vs. 37.1%, HR 1.04, p=0.25) Serious adverse events possibly or definitely related to the intervention Higher rates in the intensive-treatment group (4.7% vs. 2.5%, HR 1.88, p<0.001) Hypotension (1.8% vs. 0.8%) Syncope (1.4% vs. 0.6%) Electrolyte abnormality (1.5% vs. 1.0%) Acute kidney injury (1.9% vs. 0.7%) Wright JT, et. al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-16.

ACCORD BP Action to Control Cardiovascular Risk in Diabetes (ACCORD) Diabetic patients with SBP 130-180 mm Hg, HgbA1c of 7.5% or more, lack of significant proteinuria, 40 years of age or older with CV disease or 55 years of age or older at high risk for CV disease (N=4733) All major antihypertensive classes used SBP target of < 120 mm Hg (N=2362) SBP target of < 140 mm Hg (N=2371) Primary outcome: composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death Mean follow up 4.7 years Cushman WC, et. al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575-85.

ACCORD BP Mean SBP at one year 139.0 119.3 mm Hg in intensive treatment group vs. 139.4 133.5 mm Hg in standard treatment group HR=0.88 1.87% per year vs. 2.09% per year 0.30% per year vs. 0.47% per year HR=0.63 Cushman WC, et. al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575-85.

ACCORD BP Serious adverse events attributed to antihypertensive treatment Higher rates in the intensive-treatment group (3.3% vs. 1.3%, p<0.001) Hypotension (0.7% vs. 0.04%) Syncope (0.5% vs. 0.21%) Bradycardia or arrhythmia (0.5% vs. 0.13%) Hyperkalemia (0.4% vs. 0.04%) Cushman WC, et. al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575-85.

SPRINT vs. ACCORD BP Sample size (9361 vs. 4733) Diabetes vs. no diabetes Blood pressure measurement technique Both used automated device Omron 907 (Omron Healthcare, Lake Forest, IL) Device takes three measurements after 5 minutes rest SPRINT measurements taken unattended vs. ACCORD BP measurements taken attended Kjeldsen, SE, et. al. Unattended blood pressure measurements in the systolic blood pressure intervention. Hypertension. 2016;67:808-812.

Blood Pressure Measurements (unattended) (attended) (unattended) Myers MG, et. al. Measurement of blood pressure in the office. Hypertension. 2010;55:195-200.

Blood Pressure Measurements (unattended) (attended) (unattended) Another recent study showed unattended office BP being 15 mm Hg lower than office BP Myers MG, et. al. Measurement of blood pressure in the office. Hypertension. 2010;55:195-200. Filipovsky J, et. al. Automated compared to manual office blood pressure and to home blood pressure in hypertensive patients. Blood Press. 2016;25:228-34.

HOPE-3 Heart Outcomes Prevention Evaluation-3 (HOPE-3) Men 55 years of age or older and women 60 years of age or older with CV risk factor(s) but no preexisting CV disease (N=14682) Randomized after 4- week run in (N=12705) Candesartan 16mg/day + HCTZ 12.5mg/day (N=6353) Placebo (N=6349) Co-primary endpoint Composite of death from CV causes, nonfatal MI, or nonfatal stroke Composite of above events plus resuscitated cardiac arrest, heart failure, or revascularization Median follow up 5.6 years Lonn EM, et. al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2009-20.

HOPE-3 Mean systolic blood pressure (SBP) 138.2 128.2 mm Hg in intervention group vs. 137.9 133.9 mm Hg in placebo group Outcome Active Treatment Placebo HR (95% CI) P-value 1 st co-primary outcome 260 (4.1) 279 (4.4) 0.93 (0.79-1.10) 0.40 2 nd co-primary outcome 312 (4.9) 328 (5.2) 0.95 (0.81-1.11) 0.51 Total stroke 75 (1.2) 94 (1.5) 0.80 (0.59-1.08) 0.14 Total MI 52 (0.8) 62 (1.0) 0.84 (0.58-1.12) 0.34 Death from any cause 342 (5.4) 349 (5.5) 0.98 (0.84-1.14) 0.78 CV death 155 (2.4) 170 (2.7) 0.91 (0.73-1.13) 0.40 Heart failure 21 (0.3) 29 (0.5) 0.72 (0.41-1.27) 0.26 Lonn EM, et. al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2009-20.

HOPE-3 Lonn EM, et. al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2009-20.

HOPE-3 No difference in the rates of adverse events leading to permanent study drug discontinuation (24.4% vs. 25.2%, p=0.33) Dizziness/lightheadedness/hypotension (3.4% vs. 2.0%, p<0.0001) Higher rates of adverse events leading to temporary study drug discontinuation in the active treatment group (26.0% vs. 24.4%, p=0.04) Dizziness/lightheadedness/hypotension (2.7% vs. 1.3%, p<0.0001) Lonn EM, et. al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2009-20.

HOPE-3 vs. SPRINT Trial Characteristics HOPE-3 SPRINT Trial design Fixed-dose regimen vs. placebo Intensive vs. standard BP control Participant recruitment International United States Racial distribution 49% Asian, 28% Hispanics, 20% White 58% White, 30% Black, 11% Hispanics CV risk Lower Higher Blood pressure measurement Automated, attended Automated, unattended SBP difference 6.0 mm Hg 14.8 mm Hg Primary endpoint 1 st co-primary: HR 0.93, 95% CI 0.79-1.10 2 nd co-primary: HR 0.95, 95% CI 0.81-1.11 HR 0.75, 95% CI 0.64-0.89 Wright JT, et. al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-16. Lonn EM, et. al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2009-20. Kjeldsen, SE, et. al. Unattended blood pressure measurements in the systolic blood pressure intervention. Hypertension. 2016;67:808-812. Lonn EM, et. al. Novel approaches in primary cardiovascular disease prevention: the HOPE-3 trial rationale, design, and participants baseline characteristics. Can J Cardiol 2016;32:311-8

What Did We Learn? Insufficient evidence to deviate from SBP goal of < 140 mm Hg set forth by the guideline General population with no DM or CKD Manual or automated office BP measurements Lower on-treatment SBP is associated with increased adverse events Hypotension Syncope Electrolyte abnormalities

Guideline Recommendations JNC 8 (2014) ESH/ESC (2013) ASH/ISH (2014) General Population < 140/90 mm Hg < 140/90 mm Hg < 140/90 mm Hg Elderly Chronic Kidney Disease Older than 60 years of age < 150/90 mm Hg Younger than 80 years of age SBP 140-150 mm Hg for most, may consider < 140 mm Hg in those who are fit DBP < 90 mm Hg Older than 80 years of age SBP 140-150 mm Hg and DBP < 90 if in good physical and mental conditions < 140/90 mm Hg < 140/90 mm Hg (SBP < 130 mm Hg when overt proteinuria is present) Older than 80 years of age < 150/90 mm Hg unless chronic kidney disease or diabetes < 140/90 mm Hg Diabetes Mellitus < 140/90 mm Hg < 140/85 mm Hg < 140/90 mm Hg James PA, et. al. 2014 Evidence-based guideline for the management of high blood pressure in adults. JAMA. 2014;311(5):507-520. Weber MA, et. al. Clinical practice guideline for the management of hypertension in the community. J Clin Hypertens. 2014;16(1):14-26. Mancia G. 2013 ESH/ESC Practice guidelines for the management of arterial hypertension. Eur Heart J. 2013;34(28):2159-219.

Trial (Year of Publication) Age for Inclusion Intervention Control Achieved BP Composite CVD Total Stroke All-Cause Mortality CV Mortality SHEP (1991) 60 or older Chlorthalidonebased regimen Placebo Intervention: 143/68 mm Hg Placebo: 155/72 mm Hg RR=0.68 (0.58 to 0.79) RR=0.64 (0.50 to 0.82) RR=0.87 (0.73 to 1.05) RR=0.80 (0.60 to 1.05) STOP- Hypertension (1991) 70-84 Beta-blocker or diuretic-based regimens Placebo Intervention: 167/87 mm Hg Placebo: 186/96 mm Hg RR=0.60 (0.43 to 0.85) RR=0.53 (0.33 to 0.86) RR=0.57 (0.37 to 0.87) Fatal MI, stroke, sudden death, and other CV death: 17 vs. 41 cases MRC-OA (1992) 65-74 Beta-blocker or diuretic-based regimens Placebo Intervention: ~150/77 (est) Placebo: ~163/83 (est) RRR=17% (2% to 29%) RRR=25% (3% to 42%) RRR=3% (-14% to 18%) RRR=9% (-12% to 27%) Syst-Eur (1997) 60 or older Nitrendipinebased regimen Placebo Intervention: 151/79 mm Hg Placebo: 161/84 mm Hg RRR=31% (p<0.001) RRR=42% (p=0.003) RRR=14% (P=0.22) RRR=27% (P=0.07) Syst-China (1998) 60 or older Nitrendipinebased regimen Placebo Intervention: 151/81 mm Hg Placebo: 159/84 mm Hg RRR=37% (p=0.004) RRR=38% (p=0.01) RRR=39% (p=0.003) RRR=39% (p=0.03) HYVET (2008) 80 or older Indapamidebased regimen Placebo Intervention: 144/78 mm Hg Placebo: 159/84 mm Hg HR=0.66 (p<0.001) HR=0.70 (p=0.06) HR=0.79 (p=0.02) HR=0.77 (p=0.06) JATOS (2008) 65 to 85 Efonidipinebased regimen SBP < 140 mm Hg Efonidipinebased regimen SBP 140-159 mm Hg Strict control: 136/75 mm Hg Mild control: 146/78 mm Hg 1.18% vs. 1.27% (p=0.78) 2.35% vs. 2.22% (p=0.77) 2.44% vs. 1.90% (p=0.22) 0.27% vs. 0.18% (p=0.53) VALISH (2010) 70 to 84 Valsartan-based regimen SBP < 140 mm Hg Valsartan-based regimen SBP 140-149 mm Hg Strict control: 137/75 mm Hg Mild control: 142/77 mm Hg HR=0.89 (0.60-1.31) HR=0.68 (0.36-1.29) HR=0.78 (0.46-1.33) HR=0.97 (0.42-2.25)

JNC 8 Recommendation James PA, et. al. 2014 Evidence-based guideline for the management of high blood pressure in adults. JAMA. 2014;311(5):507-520.

Hazard ratio SPRINT 1 0.89 0.8 0.6 0.75 0.73 0.66 0.67 0.57 0.6 0.62 0.62 0.72 0.4 0.2 0 CV 1⁰ outcome All-cause mortality CV mortality Heart failure Stroke* Overall Age 75 Wright JT, et. al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-16. Williamson JD, et. al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged 75 years. JAMA 2016;315:2673-82.

HOPE-3 First Co-Primary Outcome Lonn EM, et. al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2009-20.

HOPE-3 Second Co-Primary Outcome Lonn EM, et. al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2009-20.

What SBP Goal Would You Like to Recommend for Elderly Hypertensives? A. < 150 mm Hg B. < 140 mm Hg C. < 120 mm Hg D. There are more factors to consider

What Else? BP measurement technique Comorbid conditions Risk for adverse reactions Frailty

Blood Pressure Measurements (unattended) (attended) (unattended) Myers MG, et. al. Measurement of blood pressure in the office. Hypertension. 2010;55:195-200.

Comorbid Conditions Diabetes mellitus Chronic kidney disease Stroke/transient ischemic attack Peripheral artery disease Metabolic syndrome Coronary heart disease Heart failure

Risk for Adverse Events Advanced Age Comorbidities Medications Adverse Events

Percentage Percentage Percentage Percentage Percentage 60 50 40 30 20 10 0 Risk for Adverse Events Serious Adverse Events (SAE) 48.4 48.3 38.3 37.1 Intensive Treatment Standard Treatment Overall Age 75 3 2 1 0 1 0 Hypotension (SAE) 2.4 2.4 Intensive 1.4 1.4 Standard Electrolyte Abnormalities (SAE) 5 4.0 4 3.1 3 2.7 2.3 2 Intensive Standard 3.0 2.3 2.4 1.7 Wright JT, et. al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-16. Williamson JD, et. al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged 75 years. JAMA 2016;315:2673-82. 4 3 2 1 0 Syncope (SAE) Intensive Standard Acute Kidney Injury (SAE) 6 5.5 4.4 4.0 4 2.6 2 0 Intensive Standard

Percentage Frailty Serious Adverse Events 70 60 50 40 30 20 10 0 Fit Less Fit Frail Intensive Treatment Standard Treatment Williamson JD, et. al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged 75 years. JAMA 2016;315:2673-82.

Percentage Frailty Cardiovascular events 7 6 5 4 3 2 1 0 Fit Less Fit Frail Intensive Treatment Standard Treatment Williamson JD, et. al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged 75 years. JAMA 2016;315:2673-82.

Summary SBP goal < 140 mm Hg (measured attended) is reasonable for the general population SBP goal of < 140 mm Hg (measured attended) is reasonable for elderly patients Risk vs. benefit for each individual patient Goal may be loosened for patients at high risk for adverse events The exact difference between manual office BP, attended automated blood pressure, and unattended automated blood pressure requires further research Intense monitoring for frail elderly

Test Questions 1. According to JNC 8, general population aged 60 years should be treated to a SBP goal of a. < 120 mm Hg b. < 130 mm Hg c. < 140 mm Hg d. < 150 mm Hg 2. True or False. In the SPRINT trial, targeting a SBP of < 120 mm Hg, as compared with < 140 mm Hg, resulted in lower rates of cardiovascular events. a. True b. False 3. Which of the following factor(s) would be important to consider in determining a SBP target for an elderly patient? a. Frailty b. Comorbid condition c. Risk for adverse events d. BP measuring technique e. All of the above

References Mozaffarian D, et. al. Heart disease and stroke statistics 2016. Circulation. 2016;133(4):e38-60. CDC. High blood pressure fact sheet. Retrieved from http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/docs/fs_bloodpressure.pdf James PA, et. al. 2014 Evidence-based guideline for the management of high blood pressure in adults. JAMA. 2014;311(5):507-520. Weber MA, et. al. Clinical practice guideline for the management of hypertension in the community. J Clin Hypertens. 2014;16(1):14-26. Mancia G, et. al. 2013 ESH/ESC Practice guidelines for the management of arterial hypertension. Eur Heart J. 2013;34(28):2159-219. Wright JT, et. al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-16. Cushman WC, et. al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575-85. Kjeldsen, SE, et. al. Unattended blood pressure measurements in the systolic blood pressure intervention. Hypertension. 2016;67:808-812. Lonn EM, et. al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2009-20. Lonn EM, et. al. Novel approaches in primary cardiovascular disease prevention: the HOPE-3 trial rationale, design, and participants baseline characteristics. Can J Cardiol 2016;32:311-8 Beckett NS, et. al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008;358:1887-98.

References Staessen JA, et. al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997;350:757-64. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA 1991;265:3255-3264. Ogihara T, et. al. Target blood pressure for treatment of isolated systolic hypertension in the elderly. Hypertension 2010;56:196-202. JATOS study group. Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS). Hypertens Res 2008;31:2115-2127. Dahlof B, et. al. Morbidity and mortality in the Swedish trial in old patients with hypertension (STOP-Hypertension). Lancet 1991;338:1281-85. MRC Working Party. Medical research council trial of treatment of hypertension in older adults: principal results. BMJ 1992;304:405-12. Williamson JD, et. al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged 75 years. JAMA 2016;315:2673-82. Myers MG, et. al. Measurement of blood pressure in the office. Hypertension. 2010;55:195-200. Filipovsky J, et. al. Automated compared to manual office blood pressure and to home blood pressure in hypertensive patients. Blood Press. 2016;25:228-34.

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