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Hypertension: Update

Meenakshi A Bhalla MD,FACC

Associate Professor of Medicine

Director Preventive Cardiology

Advanced Heart Failure and Transplant Cardiology

University of Kentucky

Faculty Disclosure

• None relevant.

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Introduction

• Why are we still talking about hypertension?

• Guidelines Discrepancy

• How low is too low?

• Define Resistant Hypertension

• What is the data, how to treat it?

Introduction

• Most common reason for office visits and use of prescription medications.

• NHANES (2005-2008) estimated 29-31% of adults with hypertension.

• Approx. 76.4 million Americans over the age ≥ 20 years have hypertension.

US trends in prevalence, awareness, treatment, and control of hypertension, 1988-2008. JAMA 2010; 303:2043. Mean systolic and diastolic blood pressure in adults aged 18 and over in the United States, 2001-2008. Natl Health Stat Report 2011; :1.

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Egan BM, Zhao Y JAMA 2010; 303:2043

Prevalence of Hypertension in United States

CV Mortality Risk Doubles withEach 20/10 mm Hg BP Increment*

*Individuals aged 40-69 years, starting at BP 115/75 mm Hg.CV, cardiovascular; SBP, systolic blood pressure; DBP, diastolic blood pressureLewington S, et al. Lancet. 2002; 60:1903-1913.JNC VII. JAMA. 2003.

CVmortality

risk

SBP/DBP (mm Hg)

0

1

2

3

4

5

6

7

8

115/75 135/85 155/95 175/105

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IHD Rates by SBP, DBP, and Age

A: Systolic Blood Pressure

40-49 years

50-59 years

60-69 years

70-79 years

80-89 yearsAge at risk:

IHD

Mo

rtal

ity

(Flo

atin

g A

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k an

d 9

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128

64

32

16

8

4

2

1

120 140 160 180

Usual SBP (mm Hg)

B: Diastolic Blood Pressure

IHD

Mo

rtal

ity

(Flo

atin

g A

bso

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Ris

k an

d 9

5% C

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32

16

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4

2

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70 80 90 100 110

Usual DBP (mm Hg)

Lewington et al. Lancet. 2002;360:1903-1913.

Age at risk:

40-49 years

50-59 years

60-69 years

70-79 years

80-89 years

Stroke mortality rates by SBP, DBP and Age

Data from Prospective Studies Collaboration, Lancet 2002; 360:1903.

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Cumulative absolute risk of CVD at five years

Jackson R, Lawes CM, etal. Lancet 2005; 365:434

Reference: Non diabetic, Non smoking, 50 yo Female with TC 154 mg/dl, HDL 62 mg/dl

Trends in the awareness, treatment & control of high blood pressure in adults in the United States

Adapted from: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003; 289:2560, and from US Trends in Prevalence, Awareness, Treatment, and Control of Hypertension 1988-2008, JAMA 2010; 303:2043.

Data for adults 18-74 yo of age with SBP ≥ 140 mm of Hg and/or DBP ≥90 mm of Hg

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Potential reasons for low rates of blood pressurecontrol

1. Access to healthcare and medications

2. Lack of adherence with long-term therapy

3. Therapeutic inertia

6.Wang TJ, Vasan RS. Epidemiology of uncontrolled hypertension in the United States. Circulation 2005; 112:1651.7.Egan BM et al. Initial monotherapy and combination therapy and hypertension control the first year. Hypertension 2012; 59:1124.

JNC 7 Classification of Hypertension

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No

No

No

Black

JNC 8 Hypertension Guideline Algorithm

Lifestyle  changes:•Smoking Cessation•Control blood glucose and lipids•DietEat healthy (i.e., DASH diet)Moderate alcohol consumptionReduce sodium intake to no more than 2,400 mg/day•Physical activityModerate‐to‐vigorous activity 3‐4days a week averaging 40 min persession.

(no diabetes or CKD) Diabetes or CKD present

Age  ≥ 60 years Age < 60 years All Ages Diabetes present 

No CKD

All Ages and Races CKD present with or without diabetes

BP Goal< 150/90

BP Goal< 140/90

BP Goal< 140/90

BP Goal< 140/90

Nonblack

Yes

Initiate thiazide or CCB, alone or combo

Initiate ACEI or ARB, alone or combo w/another class

Reinforce lifestyle and adherenceAdd a medication class not already selected (i.e. beta blocker, aldosterone antagonist, others) and titrate 

above medications to max (see back of card)

Initiate thiazide, ACEI, ARB, or CCB, alone or in combo

Reinforce lifestyle and adherenceTitrate meds to maximum doses, add anothermed and/or refer to hypertension specialist

Yes Continue tx and monitoring

At blood pressure goal?

Initial Drugs of Choice for Hypertension• ACE inhibitor (ACEI)• Angiotensin receptor blocker (ARB)• Thiazide diuretic• Calcium channel blocker (CCB)

At blood pressure goal?

Reference: James PA, Ortiz E, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: (JNC8). JAMA. 2014 Feb 5;311(5):507-20

Reinforce lifestyle and adherenceTitrate medications to maximum doses or consider adding another medication  (ACEI, ARB, CCB, Thiazide)

At blood pressure goal? Yes

Adult aged ≥ 18 years with HTN Implement lifestyle modifications

Set BP goal, initiate BP‐lowering medication based on algorithm

General Population

Strategy Description

A Start one drug, titrate to maximum dose, and then add a second drug.

B Start one drug, then add a second drugbefore achieving max dose of first

C Begin 2 drugs at same time, as separate pills or combination pill. Initial combination therapy is recommended if BP is greater than 20/10mm Hg above goal

Compelling Indications

Indication Treatment Choice

Heart Failure ACEI/ARB + BB + diuretic + spironolactone

Post –MI/Clinical CAD ACEI/ARB AND BB

CAD ACEI, BB, diuretic, CCB

Diabetes ACEI/ARB, CCB, diuretic

CKD ACEI/ARB

Recurrent stroke prevention ACEI, diuretic

Pregnancy labetolol (first line), nifedipine, methyldopa

Beta‐1 Selective Beta‐blockers – possibly safer in patients with COPD, asthma, diabetes, and peripheral vascular disease:•metoprolol•bisoprolol•betaxolol•acebutolol

Drug Class Agents of Choice Comments

Diuretics HCTZ 12.5‐50mg, chlorthalidone 12.5‐25mg, indapamide 1.25‐2.5mg triamterene 100mgK+ sparing – spironolactone 25‐50mg, amiloride 5‐10mg, triamterene 100mg

furosemide 20‐80mg twice daily, torsemide 10‐40mg

Monitor for hypokalemiaMost SE are metabolic in natureMost effective when combined w/ ACEI Stronger clinical evidence w/chlorthalidoneSpironolactone ‐ gynecomastia and hyperkalemiaLoop diuretics may be needed when GFR <40mL/min

ACEI/ARB ACEI: lisinopril, benazapril, fosinopril and quinapril 10‐40mg, ramipril 5‐10mg, trandolapril 2‐8mgARB: candesartan 8‐32mg, valsartan 80‐320mg, losartan 50‐100mg, olmesartan 20‐40mg, telmisartan 20‐80mg

SE: Cough (ACEI only), angioedema (more with ACEI), hyperkalemiaLosartan lowers uric acid levels; candesartan may prevent migraine headaches

Beta‐Blockers metoprolol succinate 50‐100mg and tartrate 50‐100mg twice daily, nebivolol 5‐10mg, propranolol 40‐120mg twice daily, carvedilol 6.25‐25mg twice daily, bisoprolol 5‐10mg, labetalol 100‐300mg twice daily,

Not first line agents – reserve for post‐MI/CHF Cause fatigue and decreased heart rateAdversely affect glucose; mask hypoglycemic awareness

Calcium channel blockers

Dihydropyridines: amlodipine 5‐10mg, nifedipine ER 30‐90mg,Non‐dihydropyridines: diltiazem ER 180‐360 mg, verapamil 80‐120mg 3 times daily or ER 240‐480mg

Cause edema; dihydropyridines may be safely combined w/ B‐blockerNon‐dihydropyridines reduce heart rate and proteinuria

Vasodilators hydralazine 25‐100mg twice daily, minoxidil 5‐10mg

terazosin 1‐5mg, doxazosin 1‐4mg given at bedtime

Hydralazine and minoxidil may cause reflex tachycardia and fluid retention – usually require diuretic + B‐blocker

Alpha‐blockersmay cause orthostatic hypotension

Centrally‐acting Agents

clonidine 0.1‐0.2mg twice daily, methyldopa 250‐500mg twice daily

guanfacine 1‐3mg

Clonidine available in weekly patch formulation for resistant hypertension

Hypertension Treatment

Reference: James PA, Ortiz E, et al. 2014 evidence‐based guideline for the management of high blood pressure in adults: (JNC8). JAMA. 2014 Feb 5;311(5):507‐20

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Comparison of International Guidelines on HTN Goals (mm Hg)

HTN Guideline Controversy; Age at which the blood pressure goal should be increased to less than 150/90 mm of Hg

Blood Pressure Management PSAP 2016

A scientific statement from the A scientific statement from the AHA/ACC/ASH. Circulation 2015

Treatment Of Hypertension in Patients with CAD; ACC/AHA guideline recommendation

1. <140/90 mm Hg reasonable target for the secondary prevention of cardiovascular events in patient with hypertension and CAD ( Class IIa; level of evidence B)

2. Lower target BP (<130/80 mm of Hg) may be appropriate in some individuals with CAD, previous MI, CVA or CAD risk equivalents ( Class IIb; level of evidence B)

3. Patients with elevated DBP and CAD with evidence of myocardial ischemia, BPshould be lowered slowly, and caution advised in decreasing DBP<60 mm Hg in any patient with diabetes or age >60 yrs. ( Class IIa; level of evidence C)

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Treatment of hypertension in patients with coronary artery disease. A scientific statement from the AHA/ACC/ASH. Circulation 2015

Antihypertensive Therapy Recommendations for Patients with Ischemic Heart Disease

How low is the Target??

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Acaa

• ACCORD

– BP question: Does a  strategy targeting systolic blood pressure (SBP) <120 mm Hg reduce CVD events compared to a strategy targeting SBP <140 mm Hg in 4,700 participants with type 2 diabetes at high risk for CVD events?

Clinical Trial Evidence of Lower SBP Goals is Unclear

Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus. The ACCORD Study Group. N Engl J Med 2010; 362:1575-1585

OutcomeIntensive 

Events (%/yr)Standard

Events (%/yr) HR (95% CI) P

CVD (Primary) 208 (1.87) 237 (2.09) 0.88 (0.73-1.06) 0.20

CardiovascularDeaths

60 (0.52) 58 (0.49) 1.06 (0.74-1.52) 0.74

Total Stroke 36 (0.32) 62 (0.53) 0.59 (0.39-0.89) 0.01

ACCORD Results are Mixed

Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus. The ACCORD Study Group. N Engl J Med 2010; 362:1575-1585

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Adverse EventsIntensive

N (%)Standard

N (%)P value

Serious AE 77 (3.3) 30 (1.3) <0.0001

Hypotension 17 (0.7) 1 (0.04) <0.0001

Syncope 12 (0.5) 5 (0.2) 0.10Bradycardia or Arrhythmia

12 (0.5) 3 (0.1) 0.02

Hyperkalemia 9 (0.4) 1 (0.04) 0.01

Renal Failure 5 (0.2) 1 (0.04) 0.12eGFR ever <30 mL/min/1.73m2 99 (4.2) 52 (2.2) <0.001

Any Dialysis or ESRD 59 (2.5) 58 (2.4) 0.93

Dizziness on Standing† 217 (44) 188 (40) 0.36

ACCORD Adverse Events

Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus. The ACCORD Study Group. N Engl J Med 2010; 362:1575-1585

• No difference in the primary outcome composite of nonfatal MI, nonfatal stroke or CVD death.

• Secondary outcome of nonfatal and fatal stroke was improved in the intensively treated verses standard groups (numbers of events small 32 Int vs 62 Std)

• Side effects of syncope and hypotension was greatest in the intensively treated group (2.6 fold)

• Hypokalemia more common in the intensively treated group

• Same number in both groups progressed to ESRD

• End of study intensively treated group had lower GFR than standard group

ACCORD- Summary

Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus. The ACCORD Study Group. N Engl J Med 2010; 362:1575-1585

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SPRINT Research Question

Examine effects of more intensive high blood pressure treatment than recommended

Randomized Controlled Trial Target Systolic BP

Intensive TreatmentGoal SBP < 120 mm of Hg

N= 4,678

Standard Treatment Goal SBP < 140 mm of Hg

N= 4,683

Total N= 9,361

Median follow up 3.26 years

SPRINT Res. Group. N Engl J Med 2015;373: 2103-2016.

• Stroke

• Diabetes mellitus

• Polycystic kidney disease

• Congestive heart failure( symptoms or EF<35%)

• Proteinuria >1 g per day

• CKD with eGFR < 20 ml/min/1.73 m²( MDRD)

• Adherence concerns

• ≥ 50 years old

• SBP 130-180 mm of Hg ( treated or untreated)

• Additional cardiovascular disease( CVD) risk

- Clinical or subclinical CVD (excluding stroke)

- CKD, defined as eGFR 20-60 ml/min/1.73 m2

- Framingham Risk Score for 10-year CVD risk ≥15%

- Age ≥75 years

Inclusion Criteria Exclusion Criteria

SPRINT Res. Group. N Engl J Med 2015;373: 2103-2016.

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SPRINT Primary Outcome and its ComponentsEvent Rates and Hazard Ratios

SPRINT Res. Group. N Engl J Med 2015;373: 2103-2016.

SPRINT Res. Group. N Engl J Med 2015;373: 2103-2016.

Serious Adverse Events (SAE) During Follow-up

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Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged ≥75

Years: A Randomized Clinical Trial

Objective: To evaluate the effects of intensive (<120 mm Hg) vs standard(<140 mm Hg) SBP in patients ≥75 years with hypertension but without diabetes.

Study Design: Patients ≥75 years who participated in SPRINT. Study duration 2010-2015.

Conclusions: Among ambulatory adults aged 75 years or older, treating to an SBP target of less than 120 mm Hg compared with an SBP target of less than 140 mm Hg resulted in significantly lower rates of fatal and nonfatal major cardiovascular events and death from any cause.

Williamson JD et al. JAMA 2016;315:2673-2682.

Summary

– Primary composite outcome (myocardial infarction, acute coronary syndrome, stroke, CHF, CV death) decreased 25% with intensive Rx.

– All cause mortality significantly lower in intensive Rx group: HR 0.73%; 95% CI 0.60 to 0.90; P=0.003.

– Hypotension, syncope, electrolyte abnormalities, and renal injury all higher in intensive Rx group (but not injurious falls).

– Application of results dependent on clinical judgment, tolerance of Rx, avoidance of associated problems, probable limitation to 4 BP medications.

– Fewer patients to meet SPRINT goals vs. 2014 but will have ↓ CV events.+

– Same intensive BP Rx benefits adults ≥75 years with ↓ CV events.#

*SPRINT Res. Group. N Engl J Med 2015;373: 2103-2016.+Ko MJ et al. J Am Coll Cardiol 2016;67:2821-2831.#Williamson JD et al. JAMA 2016;315:2673-2682.

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Resistant Hypertension

• Defined as either a BP of ≥140/90 mm of Hg while using optimally dosed antihypertensive agents from 3 different drug classes( including a diuretic); or blood pressure that requires 4 or more medications to achieve control

• Differentiate from Pseudo resistance

- Inaccurate BP measurements

- Poor adherence to BP medications

- Suboptimal antihypertensive therapy i.e inadequate

doses or exclusion of diuretic.

- White coat resistance ( 35% in Spanish study- well controlled

via ambulatory monitoring)

Causes Of True Resistant Hypertension

• Extracellular volume expansion

• Increased sympathetic activation

• Ingestion of substances ex NSAIDs/stimulants

• Secondary or contributing causes of hypertension.

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Treatment; General Principles

• Identify and treat secondary hypertension

• Stop medications that raise the blood pressure

• Out-of-office blood pressure monitoring

• Non-pharmacologic therapy

Pharmacological Therapy

• Diuretics: Persistent volume expansion contributes to resistant hypertension, even among patients who have been on conventional doses of thiazides.

• Mineralocorticoid Receptor Antagonists: provide significant antihypertensive benefit when added to existing multiple-drug regimens in patients with

resistant hypertension.

Gaddam KK et al. Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistentintravascular volume expansion. Arch Intern Med 2008; 168:1159.

Chapman N et al. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension 2007; 49:839.

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EXPERIMENTAL THERAPIES

• Catheter-based radiofrequency ablation of renal sympathetic nerves ( renal denervation) has not been established in patients with resistant hypertension

• A blinded randomized trial (SYMPLICITY-HTN-3) failed to demonstrate benefit.

EXPERIMENTAL THERAPIES

• Electrical stimulation of carotid sinus baroreceptors- or baroreflex activation therapy (BAT), may decrease blood pressure in patients with resistant HTN.

• Rheos Pivotal Trial failed in two of its five primary endpoints, it remains unapproved by the FDA for the indication of resistant

hypertension in the United States.Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: Bisognano JD etal J Am Coll Cardiol.2011;58(7):765

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Differences in LV mechanics drive differential response to therapy in HFpEF and HFrEF

Margaret M. Redfield et alPflugers Arch. 2014 Jun; 466(6): 1037–1053.

Conclusions

• There is Much Established Benefit from the Treatment of Hypertension.

• The age at which the goal BP< 150/90 mm of Hg remains controversial.

• Selection of the Optimal Regimen Requires Experience, Judgement, Trial/Error.

• There is diminishing support for starting with β-blocker.

• Aggressive blood pressure target of 120/80 mm of Hg safe in carefully monitored patients.

• Direct renal artery surgery has not had good results.

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Not at goal BP <140/90,or <130/80 for diabetes, CKD

or CAD, or <120/80 for LV dysfunction

Lifestyle Modifications

Initial Drug Choices

No Compelling Indications Compelling Indications

Stage 1 HTN1. Thiazides for

most2. Consider ACEI,

ARB, BB, CCB or combo

Stage 2 HTNTwo-drug combo for most; usually

thiazide and ACEI, ARB, BB,

or CCB

Drugs for compelling indications; others as

needed