Hypertension in the Era of ACC/AHA:

Practice Changing Evidence and

Recommendations

Gerald W. Smetana, M.D., MACP

Division of General Medicine

Beth Israel Deaconess Medical Center

Professor of Medicine

Harvard Medical School

COPYRIGHT

Goals

• ACC/AHA 2017: new recommendations and controversies

• >130/80 is now hypertension

• USPSTF: How to diagnose hypertension

• Importance of white coat hypertension

• Chlorthalidone preferred over HCTZ

• Mixed results for ARBs

• Risks of alpha-blockers and beta-blockers

• Goal bp <130/80 for most patients

• Approach to resistant hypertension

• Expanding role for spironolactone and labetalol

COPYRIGHT

All Drugs that Lower Blood

Pressure Do Not Equally Reduce

Cardiovascular Risk

>130/80 is Now Hypertension

COPYRIGHT

Case: Mr. Dash

• 53 year-old man

• Resident of the MFA

• Elevated cholesterol

• PAD by exam

• 15 year history of hypertension

• On HCTZ, losartan

• Office bp 138/88

• He wants to know: Is this best regimen for me?

COPYRIGHT

NHANES 2016: Prevalence of

Hypertension ( >140/90) in U.S.

https://www.cdc.gov/nchs/products/databriefs/db289.htm

COPYRIGHT

2017 ACC/AHA/AAPA/ABC/ACPM/AGS/

APhA/ASH/ASPC/NMA/PCNA

Guideline for the Prevention, Detection, Evaluation,

and Management of High Blood Pressure in Adults

Whelton PK, Carey RM, Aronow WS, et al. Hypertension 2017;71:e13COPYRIGHT

ACC/AHA 2017: Four Core Questions

1 Is self-directed monitoring of BP and/or ambulatory BP monitoring superior to office-based measurement of BP for 1) preventing adverse outcomes for which high BP is a risk factor and 2) achieving better BP control?

2 What is the optimal target BP on antihypertensive therapy?

3 Do various antihypertensive drug classes differ in their comparative benefits and harms?

4 Does initiating treatment with monotherapy versus 2 drugs (including fixed-dose combination therapy) differ in comparative benefits and/or harms on specific health outcomes?

COPYRIGHT

New BP Classifications

SBP And / Or DBP

Normal < 120 and < 80

Elevated 120-129 and < 80

Stage 1 Hypertension

130-139 or 80-89

Stage 2 Hypertension

≥ 140 or ≥ 90

ACC/AHA 2017

COPYRIGHT

Prevalence of Hypertension Based on New and Old BP Thresholds

SBP/DBP ≥130/80 mm Hg or

Self-Reported

Antihypertensive Medication†

SBP/DBP ≥140/90 mm Hg or Self-

Reported Antihypertensive

Medication‡

Overall, crude 46% 32%

Men(n=4717)

Women(n=4906)

Men(n=4717)

Women(n=4906)

Overall, age-sex

adjusted

48% 43% 31% 32%

Age group, y

20–44 30% 19% 11% 10%

45–54 50% 44% 33% 27%

55–64 70% 63% 53% 52%

65–74 77% 75% 64% 63%

75+ 79% 85% 71% 78%

Race-ethnicity

Non-Hispanic White 47% 41% 31% 30%

Non-Hispanic Black 59% 56% 42% 46%

Non-Hispanic Asian 45% 36% 29% 27%

Hispanic 44% 42% 27% 32%

COPYRIGHT

White Coat Hypertension:

A Pre-Hypertensive State

• 2015 persons

• Normotensive (52%) Hypertensive (23%) White coat (25%)

• Divided white coat into true (all home reads normal) and partial (at least one home bp elevated)

• 16 years of followup

Hypertension 2013;62:168

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

Normotensive True White Coat Partial White Coat

Incidence of New Onset

Hypertension Over 16 years

COPYRIGHT

Is White Coat Hypertension Benign? Current

Recommendations for No Rx Re-Examined

1

0.76

2.242.36

10.9

1.23

2.8

0

0.5

1

1.5

2

2.5

3

Normotension Controlled HTN White Coat HTN Sustained HTN

Hazard

Ratio

Hazard Ratio Compared to Normotension as Reference. Mean F/u 4.7 years

All Cause Mortality CV Mortality

NEJM 2018;378:1509

COPYRIGHT

Recommendation Statement from

USPSTF on Screening for HTNAnn Intern Med November 17, 2015

1. Recommend screening for high blood pressure in adults ≥ 18 years. Screen yearly

beginning at age 40

(Grade A)

2. Recommend obtaining measurements outside of the clinical setting before starting

treatment. Ambulatory 24-hour measurements preferred. Casual home monitoring acceptable

(Grade A)

COPYRIGHT

Equivalent Bp Values by Office, 24- Hour

ABPM, and Home Monitoring (HBPM)

ACC/AHA 2017

Office HBPM Daytime

ABPM

Nighttime

ABPM

24-Hour

ABPM

120/80 120/80 120/80 100/65 115/75

130/80 130/80 130/80 110/65 125/75

140/90 135/85 135/85 120/70 130/80

160/100 145/90 140/90 140/85 145/90

Stage 1

COPYRIGHT

ACCORD: No Benefit in Composite Outcome

with Lower Target BP in Diabetic Patients

NEJM 2010;362:1575

N= 4733

Target sbp120 vs 140

ADA / JNC-8

Target bp <

140/90

COPYRIGHT

SPRINT Study of Optimal BP Targets: Is this

a Game Changer?

• Age > 50

• Systolic bp 130-180

• Elevated CV risk:

– Clinical or subclinical CV disease

– CKD with eGFR 20-60

– Framingham 10-year risk ≥ 15%

– Age > 75 years

• Exclusions:

– Diabetes

– Prior stroke

• Randomly assigned to:– Sbp 140 mm Hg

– Sbp 120 mm Hg

• Drug choice left to clinician

• Median follow up 3.3 years (stopped early)

NEJM 2015;373:2103N = 9361 patients

COPYRIGHT

Systolic Blood Pressure in the Two Treatment

Groups over the Course of the Trial

COPYRIGHT

Lower Target BP Reduced Composite

Outcome and Mortality

COPYRIGHT

Other Findings

• Non-significant reduction in composite outcome for:

1. Women

2. Previous CKD

3. Black/Hispanic

4. Previous CV disease

• Adverse events more common at systolic bp 120

1. Hypotension

2. Syncope

3. AKI

4. Hyponatremia

5. Hypokalemia

• Average 2.7 drugs in intensive group

COPYRIGHT

Do ACCORD and SPRINT Actually Differ?

NEJM2015;373:2175

COPYRIGHT

ACP 2017 Guidelines on Rx of

Hypertension in Adults > 60 Years Old

1. Initiate treatment if systolic bp persistently ≥ 150 mm Hg to achieve a target systolic bp of < 150 mm Hg

2. Initiate or intensify pharmacologic treatment if a history of stroke or TIA to achieve a target systolic bp of < 140 mm Hg

3. Initiate or intensify pharmacologic treatment in some adults at high CV risk, based on individualized assessment, to achieve a

target systolic bp of < 140 mm Hg

Ann Intern Med 2017;166:430

COPYRIGHT

ACC/AHA 2017: When to Initiate

Medication and to What Goal?

Patients BP Threshold to

Initiate Rx

Target BP

for Rx

Secondary Prevention

• Clinical CVD ≥ 130/80 < 130/80

Primary Prevention

• 10 year CVD risk of ≥ 10%

≥ 130/80 <130/80

• 10-year CVD risk < 10%

≥ 140/90 <130/80 “reasonable”

COPYRIGHT

Medications

“Man has an inborn craving for medicine… The desire to take medicine is one feature which distinguishes man, the animal, from his fellow creatures… Even in minor ailments, which would yield to dieting or to simple home remedies, the doctor’s visit is not thought to be complete without the prescription.”

William Osler 1895

COPYRIGHT

TRANSCEND: Telmisartan Does Not Reduce

CV Endpoints if Intolerant to ACEi

• 5926 high risk patients

• Existing CV disease or diabetes

• End organ disease

• Intolerant to ACEi

• Key exclusions:

– CHF

– Sbp > 160

– CKD

• Randomized to telmisartan 80 mg or placebo

HR 0.92, p = 0.22

Placebo

Telmisartan

Endpoint = CV Death + MI + Stroke + CHF Admit

Lancet 2009;372:1174

COPYRIGHT

NAVIGATOR: Valsartan Does Not Reduce CV

Risk For Patients with Glucose Intolerance

• N=9306

• Impaired fasting glucose

• Established CV disease or CV risk factors

• 77% were hypertensive

• Valsartan 80-160 mg qd vs placebo

NEJM 2010;362:1477

COPYRIGHT

HOPE 3: No Hope for ARB’s:

Another Negative Trial

• N = 12,705 Primary prevention

• Men > 55 yo, Women > 65 yo

• At least one CV risk factor

• Candesartan 16 mg/HCTZ 12.5 vs. placebo

• Mean bp decrease 6.0/3.0 mm Hg

Outcome: Death from CV disease, MI, stroke, arrest, revascularization, CHF

NEJM 2016;374:2009

COPYRIGHT

Criticisms of HOPE 3

• Results reported as no benefit of Rx for HTN in intermediate risk patients

• Baseline bp 138/82 mm Hg (SD 15/9)

• Only 1/3 of patients had HTN at baseline

• Significant reductions in outcomes in the tertile with highest baseline bp

• Used submaximal fixed low dose for both HCTZ and candesartan (1/2 of max dose)

• Selected HCTZ rather than chlorthalidone

• This was another negative ARB trial

COPYRIGHT

ACEi + ARB. More is Not Always Better:

No Difference in Composite CV Endpoint

ONTARGET

Trial

•25,620 patients

•≥ 55 y.o.

•CAD

•PVD

•CVA or TIA

•DM with end organ damage

NEJM 2008;358:1547

COPYRIGHT

Combination Therapy: More Adverse

Events Despite No Benefit

0

0.5

1

1.5

2

2.5

3

Hypotensive Sx Syncope Renal Impairment

Ramipril Telmisartan Both

RR v

ers

us R

am

ipril

= p <0.05

COPYRIGHT

Renin/Angiotensin/Aldosterone

Suppression: Conclusions

• ACEi reduce CV risk to same degree as diuretics

• ACEi are appropriate first-line agents

• ARB’s comparable to ACEi in ONTARGET

• ARB’s are not effective when ACEi intolerant or if glucose intolerance

• Pending further study, would move ARBs to second line status

• This is controversial. ACC/AHA endorses ARBs

• Do not use aliskiren

COPYRIGHT

Hypertensive

patients ≥ 55 yrs

with at least one

other CV risk

factor

Consent /

Randomize

(42,418)

Amlodipine

Chlorthalidone

Doxazosin

Lisinopril

Eligible for lipid-

lowering

Not eligible for

lipid-lowering

Consent / Randomize (10,355)

Pravastatin Usual care

Follow for CHD until death or end of study (mean 4.9 years)

ALLHAT JAMA 2002;288:2981-2997

COPYRIGHT

17.3%16.8%

0%

5%

10%

15%

20%

All Cause Mortality

RR = 0.96

p = 0.20

Chlorthalidone vs. Amlodipine:

Lower CHF Rates

Chlorthalidone Amlodipine

7.7%

10.2%

0%

5%

10%

15%

Heart Failure

RR = 1.38

p < 0.001

Chlorthalidone Amlodipine

COPYRIGHT

5.6%

6.3%

0%

2%

4%

6%

8%

10%

17.3% 17.2%

0%

5%

10%

15%

20%

All Cause Mortality

RR = 1.00

p = 0.90

Chlorthalidone vs Lisinopril:

Lower CHF and Stroke Rates

Chlorthalidone Lisinopril

7.7%

8.7%

0%

5%

10%

15%

Heart Failure

RR = 1.19

p < 0.001

Chlorthalidone Lisinopril Chlorthalidone Lisinopril

Stroke

RR = 1.15

p = 0.02

COPYRIGHT

Meta-Analysis: Fewer CV Events for

Chlorthalidone than HCTZ

• Systematic review

• Studies include chlorthalidone or HCTZ in one arm

• N =9 studies

• Mean bp reduction greater for CTD than HCTZ

• Lower CV rates for CTD even after controlling for bp

Outcome for Chlorthalidone when

Compared to HCTZ

Outcome Drugadjusted

RR

Bp adjusted

RR

Mortality 0.94

Stroke 0.77

Total CV events

0.79* 0.82*

CHF 0.77*

Hypertension 2012;59:1110

COPYRIGHT

Which Diuretic to Choose?

• AHA/ACC: one of 4 choices for initial Rx

• One of two choices for African American patients

• Chlorthalidone is twice as potent as HCTZ

• Longer half life than HCTZ of 24 hours

• More effective at lowering night time bp

• Most positive diuretic trials have used chlorthalidone

• Chlorthalidone should now become our

preferred diuretic for Rx of hypertension

• Start at 12.5 mg daily. Do not exceed 25 mg qd

• Increased hypokalemia – check K+ in 2 weeks

COPYRIGHT

Cu

mu

lativ

e e

ve

nt ra

te

20% Risk Reduction

Time to 1st CV morbidity/mortality (days)

p = 0

ACEI / HCTZ

CCB / ACEI650

526

.0002

ACCOMPLISH: ACEi/CCB vs. ACEi/HCTZ

CCB Based Regimen is Superior

NEJM 2008;359:2417

COPYRIGHT

Calcium Channel Blockers: Recommendations

• Some conflicting data

• Higher CHF rates in ALLHAT

• ACCOMPLISH strongest data yet

• May be superior as part of combination Rx

• Good data for systolic HTN in elderly

• I am now moving CCBs up to a 1st line therapy

COPYRIGHT

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0 1 2 3 4

Cu

mu

lati

ve P

rim

ary

Even

t

Rate

Years of Follow-up

doxazosin

chlorthalidone

Doxazosin Inferior to Chlorthalidone

C: 15,268

D: 9,067

12,990

7,382

9,443

5,285

4,827

2,654

2,010

1,083

Rel Risk

1.25

p < 0.0001

95% CI

1.17-1.33

ALLHAT

JAMA 2000;283:1967

COPYRIGHT

Cochrane 2017: b Blockers Are No More

Effective than Placebo for Total Mortality

Cochrane Database 2017: Issue 1

COPYRIGHT

Cochrane: b Blockers Reduce Stroke Risk

Less than Other Antihypertensive Drugs

COPYRIGHT

Beta-Blockers: Recommendations

• Do not use as first line or second line treatment for hypertension

• Consider if three or more drugs required as part of multi-drug regimen for patients with drug intolerances and limited options

• Probably a class effect but most negative trials are for atenolol

• These recommendations apply only to primary prevention

COPYRIGHT

Cochrane Review: Efficacy of 1st Line

Treatments for Hypertension

Cochrane Library 2018, Issue 4

Class Mortality Stroke CHD CV

Events

Thiazides 0.89 0.68 0.72 0.70

Beta blockers

0.96 0.83 0.90 0.89

CCB 0.86 0.58 0.77 0.71

ACEi 0.83 0.65 0.81 0.76

COPYRIGHT

Significant Benefits: Only Thiazides and

ACEi Reduce All CV Endpoints

Cochrane Library 2018, Issue 4

Class Mortality Stroke CHD CV

Events

Thiazides

Beta blockers

CCB

ACEi

COPYRIGHT

One Third of Patients with Resistant

Hypertension Have White Coat Hypertension

Hypertension 2011;57:898

Resistant HTN =Uncontrolled despite

3 drugs including diuretic

COPYRIGHT

Resistant Hypertension: Treatment Strategies

• Effective combinations

– ACEi/diuretic

– ACEi/CCB

• Change HCTZ to chlorthalidone

• Add spironolactone

• Add furosemide if CKD

• Third line strategies for severe essential hypertension

– Labetalol

– Carvedilol

– Clonidine

– Dual CCB’s

– Hydralazine

– Minoxidil

COPYRIGHT

ASCOT: Spironolactone Effectively

Lowers BP

Systolic BP, 156.9

Diastolic BP, 85.3

Systolic BP, 135.1

Diastolic BP, 75.8

0

20

40

60

80

100

120

140

160

180

Systolic BP Diastolic BP

Non-Randomized: n=1411

Pre-Rx Post-Rx

Hypertension 2007;49:839

COPYRIGHT

RCT: Spironolactone Superior to Bisoprolol

and Doxazocin for Resistant Hypertension

Lancet: 2015;386:2059

N= 335

Resistant bp despite

max tolerated of 3

drugs (ACEi or ARB,

CCB, and Thiazide)

Rotated through each of 3 drugs as

add-on Rx over 6

and 12 weeks

Note: 2% incidence of K+ > 6.0

COPYRIGHT

ACC/AHA 2018 Guideline: Resistant

Hypertension Management

Step 1

• Exclude white coat, 2nd causes. Maximize 3-drug regimen

Step 2

• Substitute chlorthalidone or indapamide for HCTZ

Step 3

• Add spironolactone or eplerenone

Step 4

• If HR > 70 add beta blocker or labetalol

Step 5

• Add hydralazine

Step 6

• Substitute minoxidil

Hypertension 2018;72:e53

COPYRIGHT

Average Wholesale Price for 1 Month Supply

Class Drug Monthly Cost 4$ Option

Diuretics Chlorthalidone12.5 mg

$16 X

(HCTZ)

β-blockers Atenolol 25 mg $8 X

CCB Nifedipine 30 mg

Amlodipine 5 mg

$28

$10 X

ACEi Lisinopril 10 mg

Enalapril 10 mg

$16

$14

X

X

ARB Valsartan 80 mg

Losartan 50 mg

$165

$13 X

Source: Rx PriceQuotes.com Jan. 2019

COPYRIGHT

Summary of Evidence

Drug class Evidence for CV

risk reduction

Compelling indications

Diuretics Yes Systolic HTN elderly, CHF

ACEi Yes LV dysfunction, post MI, CKD, albuminuria

CCB Yes Systolic HTN elderly

ARB Mixed LV dysfunction

Diabetes with albuminuria

Beta-blockers Inferior Post MI

LV dysfunction

Alpha blockers Inferior None

Renin inhibitor Inferior None

COPYRIGHT

Mr. Dash: What Should We Recommend?

• Change HCTZ to chlorthalidone

• Change losartan to ACEi or CCB

• Bp target < 130/80 (SPRINT eligible, > 10% CV risk per AHA/ACC)

COPYRIGHT

What is New that Should Change Our

Practice?

• >130/80 is now Stage I hypertension• Confirm all elevated office bp values with home

measurement before treatment. • Diagnosis thresholds differ for home readings

• Don’t use beta blockers or alpha blockers

• Don’t use ACEi and ARB together

• ARBs are possibly inferior

• Goal for drug Rx < 130/80 for most patients

• Consider white coat hypertension if apparently resistant hypertension

• Spironolactone and labetalol for resistant hypertension

COPYRIGHT

All Drugs that Lower Blood

Pressure Do Not Equally Reduce

Cardiovascular Risk

>130/80 is Now Hypertension

COPYRIGHT