PRESSURED ON A Goal:

Finding the Appropriate Blood Pressure Limits for Hypertensive Non-Diabetic Elderly Patients

Kim Vo, Pharm.D. PGY 1 Pharmacy Resident

Central Texas Veterans Health Care System The University of Texas at Austin College of Pharmacy

January 29, 2016

Learning Objectives:

1. Explain the relationship between SBP and DBP in cardiovascular risk 2. Identify the types of HTN and risk factors 3. Be able to determine the importance of when to target SBP, DBP, and PP 4. Analyze the different BP goals in available guidelines, statements, and literature 5. Formulate a recommendation regarding treatment goals for BP in non-diabetic elderly

patients with HTN

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I. Epidemiology1,2,3 a. Approximately 70 million America adults have high BP b. Only about half (~52%) of people with high BP have their condition under control c. More than 360,000 American deaths in 2013 included high BP as a primary or contributing cause

II. Hypertension is one of the major risk factors for cardiovascular events4,5

a. Death from ischemic heart disease and stroke increases linearly with BP levels b. Every 20 mm Hg systolic or 10 mm Hg diastolic increase equals a doubling in mortality c. CHD and stroke mortality rate increases with both higher blood pressures and older ages

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III. Types of Hypertension6 a. Primary HTN – “Essential” – no identifiable cause

i. Risk factors: age, obesity, family history, race, diet, physical inactivity, DM, HLD, personality traits, and depression.

b. Secondary HTN – other identifiable causes i. Disease states: primary renal diseases, primary aldosteronism, obstructive sleep apnea,

pheochromocytoma, Cushing’s Syndrome ii. Illicit drug use, nicotine, and caffeine influences

iii. Medications: NSAIDs, antidepressants, decongestants, EPO, stimulants, oral contraceptives c. White coat HTN – BP consistently elevated by office readings but not based on out-of-office readings d. Masked HTN – BP that is consistently elevated by out-of-office measurements but does not meet criteria

for hypertension based upon office readings e. Moderate to severe hypertensive retinopathy – grades III and IV hypertensive retinopathy refers to

specific pathophysiology changes that may be associated with marked HTN f. Hypertensive urgency – severe HTN BP systolic >180 or diastolic >120 mm Hg without evidence of acute

end-organ damage g. Hypertensive emergency – severe HTN BP systolic >180 or diastolic >120 mm Hg with acute end-organ

damage

IV. Pathophysiology of Hypertension in the Elderly7 a. Changes in arterial structure and function with age b. The large arteries stiffen, which increases the pulse wave velocity and the SBP c. Autonomic dysregulation can occur: increased RAAS system or increased sympathetic nervous system d. Renal dysfunction

V. Diagnosis8-15

a. Current method: track 2-3 readings at several medical appointments b. Diagnosis made when systolic or diastolic readings are consistently higher than 140/90 mm Hg c. JNC 7 - With data on lifetime risk of hypertension, “prehypertension” was introduced

i. Diagnostic procedures and labs 1. For example: 12-lead ECG, urinalysis, blood glucose and hematocrit, creatinine

d. USPSTF – ABPM is the best method for diagnosing hypertension i. ABPM – small, portable BP monitoring devices that records BP at regular intervals over 12 to 24

hours while patients go about their normal activities and while they are sleeping ii. HBPM may also be reasonable confirmatory method and elevated BP with HBPM has shown

significant association with increased risk for cardiovascular outcomes e. Debated

i. Ambulatory Blood Pressure Monitoring in the Predication of Cardiovascular Events and Effects of Chronotherapy: Rationale and Design of the MAPEC study

VI. Classification of Blood Pressure per JNC 716 BP classification SBP mm Hg DBP mm Hg Normal <120 And <80 Prehypertension 120-139 Or 80-89 Stage 1 hypertension 140-159 Or 90-99 Stage 2 hypertension ≥ 160 Or ≥ 100

VII. JNC 817 – Refer to Appendix II for rated evidence (pg. 15)

a. Patients 60 years or older, start treatment in BP >150 mm Hg systolic or >90 mm Hg diastolic (Grade A)

b. Patients less than 60 years of age, initiate to lower BP at DBP ≥ 90 mm Hg i. Grade A for ages 30-59 years old

ii. Grade E for 18-29 years old c. Patients less than 60 years of age, initiate to lower BP at SBP ≥ 140 mm Hg (Grade E) d. Patients ages 18 and up with CKD or DM initiate to lower BP

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e. In nonblack patients – initial treatment: thiazide-type diuretic, CCB, ACEi, ARB (Grade B) f. In general black patients (including DM) – initial treatment: thiazide-type diuretic, CCB (Grade B

without DM, Grade C with DM) g. Patients >18 years old with CKD – initial treatment: ACEi or ARB regardless of race or DM (Grade B)

VIII. Impact on Treatment Eligibility – JNC 7 to JNC 818

a. Group: 18-59 years old in the U.S. – decreased from 20.3% to 19.2% b. Group: ≥ 60 years old in the U.S. – decreased from 68.9% TO 61.2% c. NHANES 2007 sample extrapolation – 70 million to 64.2 million people need hypertensive medications

(difference of 5.8 million U.S. adults) d. Overall: despite these differences, the numbers of adults with above-goal and untreated BP remained high

IX. Diastolic versus Systolic targets19-27

a. Diastolic hypertension predominates before 50 years of age b. Systolic hypertension predominates after 50 years of age c. Rise in SBP continues throughout life d. DBP rises until approximately 50 years old and levels over the next decade

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e. J or U- curve phenomenon i. Consistent J-shaped relationship for cardiac events and diastolic pressure

f. Three-fourths of PCPs failed to initiate antihypertensive therapy in older individuals with SBP of 140-159 mm Hg.

g. Most PCPs did not pursue control less than 140 mm Hg h. Pulse pressure = SBP – DBP

X. Goals of Therapy28

a. To reduce cardiovascular and renal morbidity and mortality Guidelines BP summary of recommendations for target BP in the elderly Classes of

recommendations/level of evidence

ESH/ESC, 2013 In patients < 80 years old may treat to systolic BP <140 mm Hg if patient is “fit” In patients > 80 years old, target systolic BP 140-150 mm Hg

Class IIbC Class IB

NICE, 2011 <140/90 mm Hg for patients < 80 years old <150/90 mm Hg for patients ≥ 80 years old

No classification or grading provided

CHEP, 2014 <140/90 mm Hg for patients < 80 years old <150/90 mm Hg for patients ≥ 80 years old

No classification or grading provided

JNC 7, 2003 <140/90 mm Hg regardless of age In blacks: Primary prevention <135/85 mm Hg Secondary prevention <130/80 mm Hg

No classification or grading provided

JNC 8, 2014 <150/90 mm Hg for patients ≥ 60 years old Grade A recommendation JNC 8 Minority View, 2014

<140/90 mm Hg for patients < 80 years old <150/90 mm Hg for “frail” patients ≥ 80 years old

No classification or grading provided

ASH/ISH, 2013 <150/90 mm Hg for patients ≥ 80 years old No classification or grading provided

ACCF/AHA, 2011 Systolic BP ≤ 140 mm Hg for all patients Systolic BP of 140-145 mm Hg for patients ≥ 80 years is acceptable if needed for tolerance

No classification or grading provided. However, authors state the target is based on expert opinion and not RCTs (elderly not defined)

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XI. Literature Review29-32 Liu L, Zhang Y, Liu G, et al. The felodipine event reduction (FEVER) study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients. J Hypertens. 2005;23:2157-72 Objective & Outcome Measures

To compare incidence of stroke and other cardiovascular events in hypertensive patients receiving a low-dose diuretic and low-dose calcium antagonist combination with those receiving low-dose diuretic monotherapy, and assess the effects of a small blood pressure difference at achieved levels lower than those achieved in previous placebo-controlled trials. Primary outcome: time to first stroke (fatal or non-fatal; hemorrhagic or ischemic or of unknown origin). Secondary outcomes: all cardiovascular events, a composite of death from cardiovascular disease, non-fatal stroke, non-fatal MI, dissecting aortic aneurysm, HF requiring additional diuretics, vasodilators or other treatment, percutaneous transluminal coronary angioplasty, or coronary by-pass graft, continues on pg. 2160 in the article.

Design - Prospective, multicenter, double-blinded, randomized, placebo-controlled, parallel-group trial.

Inclusion/ Exclusion Criteria

Inclusion Criteria 1. Age 50-79 years old

a. 1) SBP 210 mm Hg or less and DBP <115 mmHg with HTN medications

b. 2) SBP 160-210 or DBP 95-115 if untreated 2. If 60 years or less, must have clinical evidence or hx

of one cardiovascular event (MI or stroke beyond the previous 6 months; stable angina or clinical evidence of coronary heart disease; CHF NYHA class II; PAD; TIA) or two cardiovascular risk factors (male sex; current smoking of more than one cigarette per day during at least 1 year; total serum cholesterol ≥ 5.7 mmol/L, 220 mg/dL, within the previous year or lipid-lowering treatment; DM, left ventricular hypertrophy by Sokolow and Lyon ECG; proteinuria dip stick+ or higher; BMI > 27 kg/m2).

3. If older than 60, may have just one event or one risk factor

Exclusion Criteria 1. Stroke or MI during the previous 6 months 2. Secondary HTN 3. Unstable angina 4. Cardiomyopathy or significant valvular disease 5. SCR > 2.0 mg/dL 6. Gout 7. Uncontrolled DM (FBG >180 mg/dL despite therapy) 8. Serious pulmonary or hepatic disease 9. Known contraindications to study drugs 10. Unwillingness to operate

Methods • HCTZ 12.5 mg daily open label for both arms • Visit 4 begins week 0 and adding felodipine 5 mg/day or placebo • Outcome incidences expressed as numbers of events and as events for 1000 patients treated for 1 year • N = 9,711 total; N = 4,841 felodipine; N = 4,870 placebo

Statistical Analysis: • P < 0.05, power 80%, and CI 95% for statistical significance • Intention-to-treat • N = 10,000 patients followed for 3 years to test the two-sided hypothesis that projected rate of 14 fatal and non-

fatal strokes per 1000 patient-years in the placebo group would be reduced by at least 25% on active treatment with felodipine = 400 strokes

• Cox regression to assess outcome differences between randomized treatment arms • Age, presence of previous stroke, TIA, MI, angina pectoris and DM used as a priori covariates for the effects of

key risk predictors at baselines • Treatment effects were measured by hazard ratios • Time-dependent Cox analysis were run to show the effect consistency over time and calculated with odds ratios

and 95% CI • Cumulative event rates over time illustrated as Kaplan-Meier curves • Log-rank test to show differences between groups in time to event • Differences in proportion of patients with an event were analyzed using chi-squared tests as well as differences

between groups in the frequency of adverse effects • SAS system version 8.2

Results Primary Outcome (full)

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Incidence of the secondary outcome, its components, and death from any cause by randomization group

Authors’ Conclusion

In moderately complicated hypertensive patients from China even a difference in SBP/DBP as small as 4/2 mm Hg, such as that induced by adding low-dose felodipine to low-dose HCTZ, is associated with very substantial reductions in the incidence of the most types of cardiovascular events. SBP below 140 mm Hg and slightly above.

Reviewer’s Evaluation

Strengths • Study design

o Blinding and randomization • Large sample size (N = 9800) • Two medications versus extra additional

medications • Looked at safety profile

Limitations • Short duration • Compared to other studies there were still some DM

patients • Generalizability – location: China • Did not set 2 blood pressure targets, just did

tighter versus not and looked at differences from baseline

Clinical Implications

Moderate reductions from goal <140 mm Hg systolic with 1-2 medications have less cardiovascular risks than above >140 mm Hg. Adverse events may not be debilitating enough to outweigh the benefits.

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Verdecchia P, Staessen J, Angeli F, et al. Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label randomised trial. The Lancet. 2009;374(9689):525-33 Objective & Outcome Measures

Tested that tight control (<130 mm Hg) compared with usual control (<140 mm Hg) of systolic blood pressure would be beneficial in non-diabetic patients with hypertension. Primary outcome: Prevalence of electrocardiographic left ventricular hypertrophy at the final 2-year visit. Secondary outcomes: composite of all-cause mortality, fatal or non-fatal MI, stroke, TIA, CHF III/IV, angina pectoris, new-onset atrial fibrillation, renal failure requiring dialysis.

Design - Randomized, controlled, open-label trial

Inclusion/ Exclusion Criteria

Inclusion Criteria 1. Age ≥ 55 years old 2. SBP ≥150 mm Hg 3. Been on antihypertensive treatment for at least

12 weeks 4. Must have at least one additional risk factors:

cigarette smoking, total cholesterol ≥93.6 mg/dL, HDL <18 mg/dL, LDL ≥61.2 mg/dL, family history, Hx of TIA or stroke, or PAD

Exclusion Criteria 1. Fasting glucose ≥ 126 mg/dL 2. Hx of DM 3. Reduced life expectancy 4. Renal dysfunction SCR > 2 mg/dL 5. Hepatic or hematological disorders 6. Valvular heart disease 7. Heart rhythm dysfunctions – atrial fibillation, etc.

Methods 1. Enrollment from 2/22/05 to 2/28/07 at 44 centers in Italy 2. Comparative groups and # enrolled per group: 1111 patients randomized 3. Computerized randomization 1:1 ratio to tight SBP <130 mm Hg or usual SBP <140 mm Hg 4. Left ventricular hypertrophy validated by Perugia criteria:

a. Modified Cornell voltage b. Left ventricular strain (inverted asymmetric T wave with flat or downsloping ST segment) c. Or a Romhilt-Estes score of 5 or more

5. Follow-up: every 4 months for 2 years – measured BP using standard sphygmomanometers 6. Open label and tailored BP meds – furosemide, ramipril, telmisartan, amlodipine, bisoprolol, transdermal

clonidine, combinations with HCTZ

Statistical Analysis: • SAS version 9.1.3 • For 85% power to show 7% absolute difference in prevalence of the two groups, need 550 patients per arm,

total of 1100 • Intention-to-treat • Z test and proportions by X2 analysis, logistic regression • Incidence of events with Kaplan-Meier survival function estimates, the log-rank test, and Cox regression

Results Rate of left ventricular hypertrophy by randomization groups at baseline and follow-up

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Incidence of the secondary outcome, its components, and death from any cause by randomization group

Adverse reactions by randomized group

Authors’ Conclusion

Tight control of SBP <130 mm Hg in non-diabetic patients with at least one additional risk factor had less ECG left ventricular hypertrophy and clinical events compared to <140 mm Hg SBP.

Reviewer’s Evaluation

Strengths • Perugia Score had a good performance • Safety profile tested • Study design

o RCT

Limitations • EKG vs ECHO in sensitivity of left ventricular

hypertrophy • Not double-blinded • Generalizability to other race • Small sample size (N = 1100) • Limited timeframe – 2 years

Clinical Implications

Aiming for lower BP goals for older patients without DM have positive outcomes and practice and studies will start to compare for different outcomes at different BP since BP goals still need to be elucidated.

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Mohebi R, Mohebi A, Ghanbarian A, et al. Is systolic blood pressure below 150 mm Hg an appropriate goal for primary prevention of cardiovascular events among elderly population? J of the American Society of Hypertension. 2014;8(7):491-7 Objective & Outcome Measures

Impact of different BP categories on risk of developing CVD and mortality and assess whether BP 150/90 mm Hg is an appropriate goal for preventing CVD among elderly population in the Middle Eastern community based cohort of the Tehran Lipid and Glucose Study (TLGS). Outcomes: Mortality data – from hospital, death certificate, verbal autopsy if needed and evaluated by committee

• MI – EKG • Stroke – new neurologic deficit for >24 hours • CHD – angiograms with lesions >50% obstruction • Unstable angina – EKG and new cardiac symptoms

Design - Prospective study, multistage cluster randomization, at three medical health centers - Cross-sectional phase of TLGS

Inclusion/ Exclusion Criteria

Inclusion Criteria 4. Age ≥ 60 years old

Exclusion Criteria 1. Missing BP data (N = 36) 2. Hx of prior CVD (N = 381)

Methods 1. Monitored March 2010 – 10 years follow-up 2. -4 Groups: 1) SBP <120 mm Hg and DBP <80 mm Hg; 2) SBP 130-139/DBP 80-89; 3) SBP 140-149 mm Hg; 4) SBP

>150 and DBP >90 mm Hg

Statistical Analysis: • SAS version 9.1.3 • For 85% power to show 7% absolute difference in prevalence of the two groups, need 550 patients per arm,

total of 1100 • Intention-to-treat • Z test and proportions by X2 analysis, logistic regression • Incidence of events with Kaplan-Meier survival function estimates, the log-rank test, and Cox regression.

Results

Authors’ Conclusion

SBP between 150 mm Hg and 140 mm Hg are still at elevated risk for CHD events. Future studies are needed to find new therapeutic measures to reduce the risk of this group.

Reviewer’s Evaluation

Strengths • Large study – subgroup: 15, 055 to 1845 • Long duration of f/u: 10 years

Limitations • Lifestyle not addressed • No adverse events included • Generalizability – Middle East Caucasians

Clinical Implications

There are studies coming out challenging the JNC 8 guidelines of <150/90 BP goal and they could include more adverse outcomes on each incremental changes in BP. This study shows there may be more risks to keep above 140 SBP.

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The SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015; 373:2103-2116

Objective & Outcome Measures

Treating hypertension reduces the risk of cardiovascular disease outcomes, including incident of stroke, myocardial infarction, and heart failure. The target for systolic BP lowering is uncertain. Evaluating reduction in cardiovascular disease risk in an intensive versus standard blood pressure target groups. Primary outcome: first occurrence of a MI, ACS, stroke, HF, or CVD death Secondary outcomes: all-cause mortality, decline in renal function or development of ESRD, dementia, decline in cognitive function, and small vessel cerebral ischemic disease, co-morbidities, quality of life, cost-effectiveness and adverse effects.

Design - Randomized, controlled, open-label trial

Inclusion/ Exclusion Criteria

Inclusion Criteria 1. Age ≥ 50 years old 2. SBP ≥ 130 mm Hg to 180 mm Hg 3. eGFR > 20 mL/min/1.73 m2 4. ACR < 600 mg/g 5. No hx of stroke or diabetes

Exclusion Criteria 1. Known secondary cause of HTN that causes concern regarding safety of the protocol 2. One minute standing SBP < 110 mm Hg 3. Proteinuria ≥ 600 mg/day 4. Arm too large or small for available devices 5. DM 6. Hx of stroke

Methods • Similar treatment algorithms to the ACCORD trial (Appendix IV, V; pg.17) • N = 9250 participants; setting: 102 clinical sites in the United States, including Puerto Rico • Participants were seen monthly (for first 3 months) and every 3 months thereafter • Recruitment will be over a 2 year period while follow-up will be for up to 6 years Statistical Analysis: • Power of study: 90% to detect a 20% effect on the primary composite endpoint of CVD mortality

and non-fatal MI, ACS, stroke, and heart failure. Results Appendix VII. Primary and Secondary Outcomes and Renal Outcomes

All subjects

Intensive N = 4678

Standard N = 4683

Hazard Ratio (95% CI)

P Value

N (%) % per year N (%) % per year Primary Outcome

243 (5.2) 1.65 319 (6.8) 2.19 0.75 (0.64-0.89) <0.001

All subjects

Intensive N = 4678

Standard N = 4683

Hazard Ratio (95% CI)

P Value

# of pts (%) % per year # of pts (%) % per year Death from any cause

155 (3.3) 1.03 210 (4.5) 1.40 0.73 (0.60-0.90) 0.003

APPENDIX VIII. Serious Adverse Events, Conditions of Interest, and Monitored Clinical Events **The mean systolic BP was 121.4 mm Hg in the intensive vs 136.2 m Hg in the standard.

Authors’ Conclusion

Targeting SBP < 120 mm Hg resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause. Some adverse events occurred significantly more frequently in the intense arm.

Reviewer’s Evaluation

Strengths • Large sample size • Diverse • Study design

Limitations • Generalizability with subset populations • Age and other comorbidities like DM • Exclusion criteria • SBP differences

Clinical Implications

Lower SBP for elderly is recommended. The concern with renal injury may limit certain patients who already have CKD or AKI. The generalizability with comorbid conditions is limited.

XII. Recommendations33, 34

a. Pharmacist’s Letter i. Follow current guidelines – JNC 8

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ii. Be open to BP <120 with PMH of MI or CKD and toleration of the patient b. UpToDate – nondiabetic adults ≥ 50 years old

i. BP using an automated oscillometric device (measuring 5-10 mm Hg lower than manual) 1. Target – BP 120-125 mm Hg systolic and <90 mm Hg diastolic (Grade 1A)

a. DM – same (Grade 2B) ii. Other methods - manual

1. Target – BP 125-130 mm Hg systolic and <90 mm Hg diastolic (Grade 1B) a. DM – same (Grade 2B)

c. My recommendations i. Based on studies: intensive therapy has shown better outcomes

1. Each study had different mean SBP goals or outcomes 2. BP <140/90 is common among most studies 3. Based on the FEVER study, small changes to even below SBP 140 had statistical

significance in fewer primary outcomes with fewer adverse effects a. NNT

4. Achieving <120/90 may be acceptable for certain patients but not all patients ii. Recommendation: to target all elderly patients SBP <140

1. Modify based on PMH (higher risk of strokes), FH, SH, lifestyle (diet and physical activity), past history of falls, medication adherence

a. Individualize b. Home BP readings > clinic readings

i. Watch for outside influences c. If patients are already at a lower BP, then without hypotension or other

cardiovascular risks, can maintain current therapy

XIII. Future Studies a. Effect of Intensive Blood Pressure Control on Progression of Coronary Atherosclerosis: Randomized

Evaluation by Intravascular Ultrasound (PREVUS) i. Purpose: evaluate the effect of intensive blood pressure control compared to standard blood

pressure control on progression of coronary atherosclerosis by intravascular ultrasound in hypertensive patients with coronary artery disease

ii. Randomized control open label iii. Primary outcome: change of percent atheroma volume measured by intravascular ultrasound iv. Estimated enrollment: 50 v. Treatment arms: SBP <120 mm Hg with losartan vs <140 mm Hg with losartan

b. Strategy for Adequate Blood Pressure Lowering in the Patients with Intracranial Atherosclerosis (STABLE-ICAS)

i. Purpose: develop adequate BP lowering strategy after subacute ischemic stroke patients with symptomatic severe intracranial atherosclerosis

ii. Randomized single blinded parallel iii. Primary outcome: the difference between final ischemic lesions volume and base ischemic lesions

of both hemisphere on fluid attenuation inversion recovery (FLAIR) magnetic resonance imaging (MRI)

iv. Estimated enrollment: 156 v. Treatment arms: SBP 110-120 mm Hg (aggressive) vs 120-140 mm Hg (modest)

c. Effect of Intense vs. Standard Hypertension Management on Nighttime Blood Pressure – an Ancillary Study to SPRINT

i. Purpose: evaluate the effect of intensive vs. standard clinic based BP targets on nighttime BP ii. Randomized open label parallel

iii. Primary outcome: BP targets on nighttime BP iv. Estimate enrollment: 600 v. Treatment arms: SBP <120 mm Hg vs SBP <140 mm Hg

d. Systolic Blood Pressure Intervention Trial: Memory and Cognition in Decreased Hypertension (SPRINT-MIND)

i. Purpose: determine the effects of reducing SBP on cognitive function ii. Randomized open label parallel

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iii. Primary outcome: the incidence of all-cause dementia will be lower in SPRINT participants assigned to the intensive SBP treatment arm compared to their counterparts assigned to the standard SBP treatment arm

iv. Estimate enrollment: 2800 SPRINT participants v. Treatment arms: SBP less than 120 mm Hg for the Intensive Group and SBP less than 140 mm Hg

for the Standard Group

XIV. Potential research a. Prospective trial evaluating the impact of reducing heart rate on CV outcomes

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38. NHLBI. Systolic blood pressure intervention trial: Memory and cognition in decreased hypertension (SPRINT-MIND). 2010 Oct. https://www.nia.nih.gov/espanol/alzheimers/clinical-trials/systolic-blood-pressure-intervention-trial-memory-and-cognition-decreased. Accessed 2016 Jan

Quick Links – Guideline and Statements • ASH guideline database - http://www.ash-us.org/About-Hypertension/Hypertension-Guidelines.aspx • JNC 7 - http://jama.jamanetwork.com/article.aspx?articleid=196589

• JNC 8 - http://jama.jamanetwork.com/article.aspx?articleid=1791497 • 2013 ESH/ESC - a. http://www.esh2013.org/wordpress/wp-content/uploads/2013/06/ESC-ESH-Guidelines-2013.pdf • KDIGO - http://www.kdigo.org/clinical_practice_guidelines/pdf/KDIGO_BP_GL.pdf • ADA - http://care.diabetesjournals.org/content/38/Supplement_1 • ACC/AHA - http://hyper.ahajournals.org/content/63/4/878.full Appendices Appendix I: Abbreviations ABPM – ambulatory blood pressure monitoring ACCF – American College of Cardiology Foundation ACEi – angiotensin converting enzyme inhibitor ACR – albumin to creatinine ratio ACS – acute coronary syndrome AHA – American Heart Association AKI – acute kidney injury ARB – angiotension II receptor blocker ASH/ISH – American Society of Hypertension/International Society of Hypertension BP – blood pressure CCB – calcium channel blocker CHEP – Canadian Hypertension Education Panel

HTN – hypertension IHD – ischemic heart disease JNC – Joint National Committee MI – myocardial infarction mm Hg – millimeter of mercury MVA – motor vehicle accident NHANES – National Health and Nutrition Examination Survey NHLBI – National Heart, Lung, and Blood Institute NICE – National Institute for Health and Clinical Excellence NIH – National Institutes of Health NSAIDS – nonsteroidal anti-inflammatory drugs OSA – obstructive sleep apnea PAD – peripheral artery disease

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CHF – congestive heart failure CKD – chronic kidney disease CVD – cardiovascular disease DBP – diastolic blood pressure DM – diabetes mellitus ECG – electrocardiogram eGFR - estimated glomerular filtration rate EPO – erythropoietin ESH/ESC – European Society of Hypertension/European Society of Cardiology ESRD – end-stage renal disease FBG – fasting blood glucose FH – family history HBPM – home blood pressure monitoring HCTZ – hydrochlorothiazide HF – heart failure HFSA – Heart Failure Society of America HLD – hyperlipidemia

PCP – primary care physician PMH – past medical history PY – Patient-years RAAS – renin angiotensin aldosterone system RCT – randomized control trial SBP – systolic blood pressure Scr – serum creatinine SH – social history TIA – transient ischemic attack USPSTF – U.S. Preventative Services Task Force

Appendix II: Rated Evidence JNC 8 A) Strong Recommendation High certainty based on evidence that the net benefit is substantial B) Moderate Recommendation Moderate certainty based on evidence that the net benefit is moderate to substantial C) Weak Recommendation At least moderate certainty based on evidence that there is a small net benefit E) Expert Opinion Insufficient evidence or evidence is unclear or conflicting, but this what the committee

recommends. Further research is recommended. N) No recommendation No recommendation for or against ESH/ESC: Classes of Recommends and Levels of Evidence Class I Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective. Is

recommended/is indicated. Class II Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or

procedure. Class IIa Weight of evidence/opinion is in favor of usefulness/efficacy and treatment should be considered. Class IIb Usefulness/efficacy is less well established by evidence/opinion and treatment may be considered. Class III Evidence or general agreement that the given treatment or procedure is not useful/effective, and in some

cases may be harmful. Level A Data derived from multiple RCTs or meta-analysis Level B Data derived from a single RCT or large non-randomized studies Level C Consensus of opinion of the experts and/or small studies, retrospective studies, or registries UpToDate Grade of Recommendation Clarity of risk/benefit Quality of Supporting Evidence Implications 1A. Strong recommendation, high quality evidence

Benefits clearly outweigh risk and burdens, or vice versa.

Consistent evidence from well performed randomized, controlled trials or overwhelming evidence of some other form. Further research is unlikely to change our confidence in the estimate of benefit and risk.

Strong recommendations, can apply to most patients in most circumstances without reservation. Clinicians should follow a strong recommendation unless a clear and compelling rationale for an alternative approach is present.

1B. Strong recommendation, moderate quality evidence

Benefits clearly outweigh risk and burdens, or vice versa.

Evidence from randomized, controlled trials with important limitations (inconsistent results, methodologic flaws, indirect or imprecise), or very strong evidence of some other research design. Further research (if performed) is likely to have an impact on our confidence in the estimate of benefit and risk and may change the estimate.

Strong recommendation and applies to most patients. Clinicians should follow a strong recommendation unless a clear and compelling rationale for an alternative approach is present.

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1C. Strong recommendation, low quality evidence

Benefits appear to outweigh risk and burdens, or vice versa.

Evidence from observational studies, unsystematic clinical experience, or from randomized, controlled trials with serious flaws. Any estimate of effect is uncertain.

Strong recommendation, and applies to most patients. Some of the evidence base supporting the recommendation is, however, of low quality.

2A. Weak recommendation, high quality evidence

Benefits closely balanced with risks and burdens.

Consistent evidence from well performed randomized, controlled trials or overwhelming evidence of some other form. Further research is unlikely to change our confidence in the estimate of benefit and risk.

Weak recommendation, best action may differ depending on circumstances or patients or societal values.

2B. Weak recommendation, moderate quality evidence

Benefits closely balanced with risks and burdens, some uncertainly in the estimates of benefits, risks and burdens.

Evidence from randomized, controlled trials with important limitations (inconsistent results, methodologic flaws, indirect or imprecise), or very strong evidence of some other research design. Further research (if performed) is likely to have an impact on our confidence in the estimate of benefit and risk and may change the estimate.

Weak recommendation, alternative approaches likely to be better for some patients under some circumstances.

2C. Weak recommendation, low quality evidence

Uncertainty in the estimates of benefits, risks, and burdens; benefits may be closely balanced with risks and burdens.

Evidence from observational studies, unsystematic clinical experience, or from randomized, controlled trials with serious flaws. Any estimate of effect is uncertain.

Very weak recommendation; other alternatives may be equally reasonable.

Appendix III. Institute of Medicine’s Standards for Developing Clinical Practice Guidelines Standard 1: Establish transparency Standard 2: Manage conflicts of interest, including full disclosure, divestment, and possible exclusion from writing guidelines Standard 3: Development of multidisciplinary, balanced writing group composition Standard 4: Use of high-quality systematic reviews that includes communication between guidelines writers and the writers of the systematic review Standard 5: Establish evidence foundation for and rating strength of recommendations Standard 6: Standardize how recommendations are articulated Standard 7: Obtain external review of guidelines, including making a near-final draft available for public comment Standard 8: Update the guidelines regularly

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Appendix IV. Treatment algorithms for the intensive group (Goal SBP <120 mm Hg)

Appendix V. Treatment algorithms for the standard group (Goal SBP <140 mm Hg)

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Appendix VI. Primary and Secondary Outcomes and Renal Outcomes – SPRINT trial

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Appendix VII. Serious Adverse Events, Conditions of Interest, and Monitored Clinical Events – SPRINT trial