hypertension in the era of acc/aha: practice changing ......even in minor ailments, which would...
TRANSCRIPT
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