HYPERTENSION: EVIDENCE-BASED UPDATE, 2013
(Waiting for JNC-8, Still!)
Barry Stults, M.D.
Division of General Medicine
University of Utah Medical Center
May, 2013
This presentation has no commercial content, promotes
no commercial vendor and is not supported financially
by any commercial vendor. I receive no financial
remuneration from any commercial vendor related to
this presentation.
HTN: DOMINANT CONTRIBUTOR TO
GLOBAL MORTALITY
Increases RR by 2.0-4.0 fold for:
• CAD, stroke, HF, PAD
• Renal failure, AF, dementia,  cognition
Attributable risk for HTN:
• Stroke
• CKD
• HF
62%
56%
49%
• MI
• Premature death
25%
24%
Aftermath:
• Shortens lifespan  5y
• $93.5 billion/y in U.S.
Circulation 2012; 125:e12
J Hum Hypertension 2008; 22:63
Hypertension 2007; 50:1006
NEWLY RECOGNIZED CONSEQUENCES OF HTN
Framingham cerebral MRI study (cross-sectional):
– 579 subjects, mean age = 39.2y
White-matter microstructural damage
• Anterior corpus callosum
 Systolic BP:
• Pre-HTN
• HTN
• Fronto-occipital fasciuli
• Fronto-thalamic fibers
Temporal lobe grey matter atrophy
 SBP before age 50 damages cerebral loci
associated with cognitive dysfunction!
Lancet Neurology 2012; 11:1039
HTN PREVALENCE, 2010: NHANES
All
• White
• Black
• Hispanic
• Age  60y
% BP  140/90
30%
29%
42%
27%
67%
- No change in HTN prevalence since 2000
• 75 million Americans have HTN
JACC 2012; 60:599
HTN CONTROL (< 140/90) RATES: 1988-2010
NHANES
All
1988
2001
2010
Healthy People
2020 Goal
Canada
2010
VA
2010
27%
29%
47%
61%
65%
76%
(40% M, 56% W)
• White
---
30%
50%
---
---
---
• Black
---
25%
41%
---
---
---
• Hispanic
---
25%
34%
---
---
---
• CVD
---
---
55%
---
---
---
• DM < 130/80
---
---
42%
---
---
---
• CKD < 130/80
---
---
39%
---
---
---
‒ No U.S. improvement since 2007!
Circulation 2012; 126:2105
CMAJ 2011; 183:1007
Circulation 2012; 125:2462
JACC 2012; 60:599
U.S. HTN CONTROL: 39 million  140/90!
- YET 85% HAVE HEALTH INSURANCE!
40% Unaware
45% Rx’d, Uncontrolled
• Older, women, obese,
AA, CKD, CVD, DM
15% Aware,
No Rx
• Younger, men, Hispanic,
 finances, 0-1 visits/y
 Screening
• Work, CC’s,
church
 Media outreach
 Access to care Pseudo-HTN
• Control for
• Insurance
BP variability
• Availability
• Measure BP
accurately
• Detect WCH
MMWR 2012; 61:703
MMWR 2011; 60:103
 Rx
 Rx
inertia
efficiency
• 65% on
1-2 drugs
Circulation 2011; 124:1046
 Pt
adherence
Can J Card 2012; 28:375
HOW LOW TO GO? TARGET BP, 2013
Guideline
General
Age  80
JNC-7, 2003
< 140/90
CHEP, 2013
CKD
DM
---
< 130/80
< 130/80
< 140/90
< 150
< 140/90
< 130/80
---
---
<140/90
if ACR <30
 130/80
if ACR ≥ 30
< 140/90
if ACR <30
 130/80
if ACR ≥ 30
< 140/90
< 150/90
---
---
ACCF/AHA, 2011
---
140-145*
---
---
ADA, 2013
---
---
---
JNC-8, 2013
?
?
?
NKF-KDIGO, 2012
NICE, 2011
*Initiate Rx if SBP  150 mm Hg
**  <130/80 in younger/↑ stroke risk pts
< 140/80**
?
Can J Card 2013; online 3/25
BMJ 2011; 343:d4891 Circulation 2011; 123:2434
Diabetes Care 2013; 36:Suppl 1:S11 Kid Int 2012; supplement 2:341
AGE  80Y: HOW LOW TO GO?
HYVET RCT, 2008: 3845 pts age  80y, SBP = 160-199
Final SBP = 157
Initial SBP = 171
Placebo
Indapamide  ACE-I
Final SBP = 143
Total Stroke
Fatal Stroke
Mortality
CHF
RRR
 30%
 39%
 21%
 64%
J-Curve concern: too low BP in very elderly?
• Optimal BP, age  80y: 140/70, INVEST RCT (post-hoc)
NEJM 2008; 358:1887
Circulation 2011; 123:2434
GOAL BP: HOW LOW FOR AGE  80y?
• INVEST RCT: BP Rx in 22,576 CAD pts
Circulation 2011; 123:2434
CKD: HOW LOW TO GO?
Systematic review, 3 RCTs: MDRD, AASK, REIN
133-141/80-86
2272 pts
130-139/80-89
< 130/80
126-130/77-80
RRR
CVD events
NS
CKD progression NS
Mortality
NS
• Subgroup with proteinuria  300-1000 mg/d*:
HR
CVD events
NS
CKD progression  24-39%
*Low quality evidence
Ann Int Med 2011; 154:541
DIABETES MELLITUS: HOW LOW TO GO?
Meta-analysis: 13 RCTs, mean achieved systolic BP
37,736 pts
< 140
 135
 130
Risk Reduction vs < 140
 135
Total mortality
Stroke
MI
ESRD/2X  Cr
 10%
 17%
NS
NS
 130
NS
 47%
NS
NS
• Target BP = 130-135 reduces mortality/stroke?
• Target BP  130 reduces stroke?
Circulation 2011; 123:2799
GOAL BP: HOW LOW TO GO?
< 140/90:
Low enough?
< 130-135?
< 110-120/60-70:
Too low, J-curve?
1 Prevention vs 2 Prevention?
SPRINT: 9000 patients, 2018 completion
• High CVD risk
• CKD
• Age  75
PODCAST, SPSSS, SHOS: Post-stroke/TIA
PLOS Medicine 2012; 9:e1001293
Hypertension 2012; 59:
Circulation 2011; 124:1700
CHALLENGES TO CLINICAL VALIDITY OF OFFICE BP
Inherent BP Variability:
 over min  months!
• 20%  SBP  10 mm Hg
over 1-2 min
• 4-5 office visits for BP to
stabilize
Inaccurate BP Measurement:
Rule, not Exception!
• 93% make technical errors
- Mean # errors = 4
“True” or usual BP Predicts CVD Risk
Out-of-office BP  Office BP for Many!
• White-coat HTN in 20-33%
• Masked HTN in 10%
Am J Hypertens 2011; 24:1073 Ann Int Med 2011; 154:781
J Gen Int Med 2012; 27:623
BP MEASUREMENT: KEY TECHNIQUES
 BP (mm Hg) if not done
Rest ≥ 5 min, quiet
 12/6
Seated, back supported
 6/8
Cuff at midsternal level
  2/inch
Correct cuff size
 6-18/4-13 if too small
 7/5 if too large
Bladder center over artery
 3-5/2-3
Deflate 2 mm Hg/sec
 SBP/ DBP
No talking during measurement
 17/13
If initial BP > goal BP:
1st reading higher
3 readings, 1 min apart
• “Alerting response”
Discard 1st, average last 2
• Reclassify 18-34% as normotensive
with last 2 readings
J Clin Hypertens 2012;14:751
Hypertension 2005; 45:142
J Gen Int Med 2012; 27:623
J Hypertens 2005; 23:697
Can J Card 2012; 28:270
RESEARCH QUALITY vs ROUTINE OFFICE BP
# of pts
Routine Clinical
Practice BP
Research Quality
Office BP
Difference
Myers, 1995
147
146/87
140/83
- 6/4
Brown, 2001
611
161/95
152/85
-9/10
Myers, 2009
309
152/87
140/80
-12/5
Graves, 2003
104
152/84
138/74
-14/8
Gustavsen, 2003
420
165/104
156/100
-9/4
Campbell, 2005
107
150/91
139/86
-11/5
Head, 2010
6817
150/89
142/82
-8/7
Burgess, 2011
181
145/85
132/79
-12/6
Study
Powers, 2011
444
145/129/Accurate measurement  BP by  10/7 mm Hg
-16/-
 2X improved HTN control rate (Powers, Burgess, 2011)
Ann Int Med 2011; 154:781
Am J Hypertens 2005; 18:1522
Hypertension 2010; 55:195
BMJ 2010; 340:1104
JASH 2011; 5:484
OUT-OF-OFFICE BP MEASUREMENT TO DX HTN?
CHEP, 2005  2013; AHA, 2008: optional OBPM vs ABPM vs HBPM
2 Office Visits: BP ≥ 180/110
Yes
or ≥ 140/90 and CVD, DM, or CKD
Dx HTN
No: BP = 140-179/90-99 and low risk
R/O White-coat HTN: 20-33%
Serial Office Visits:
• 3 if BP  160/100
• 5 if BP = 140-159/90-99
24h ABPM:
• Daytime BP  135/85
• 24h BP  130/80
BP < 135/85
Home BPM x 7d
• Mean BP  135/85
Dx HTN
Can J Card 2012; 28:270
HOME BPM: PROS AND A FEW CONS!
Pros vs Office BPM:
• More accurate HTN Dx in most studies
‒ More measurements  out-of-office measurements
• Better CVD prediction: similar to ABPM
‒ Meta-analysis: 8 studies; 17,688 pts; 3.2-10.9y FU
• Improves BP control:  systolic BP 3.4-8.9 mm Hg
‒ AHRQ 2012 systematic review: 6 high quality studies
Cons vs Office BPM:
• Not yet proven to  CVD events better
• Expense/inadequate patient training
J Hypertens 2012; 30:449, 463, 1289
Hypertens Res 2012; 35:750
AHRQ, 2012; #45
HBPM MONITOR VALIDATION:
NOT ALWAYS ACCURATE!
For populations: AAMI, BHS, IP validation protocols
• Omron, A&D Medical (Lifesource), MicroLife, other
• Listings of validated devices:
www.hypertension.ca/devices-endorsed-by-hypertension-canada
www.bhsoc.org/blood_pressure_list.stm
www.dableducational.org
For individuals: office validation at purchase and q 1y
• Sequential method, 1 arm: < 5 mm Hg diff., last 2 tests:
Osc D – Osc D – Ausc D – Osc D – Ausc D
• Simultaneous method, 2 arms: < 5 mm Hg diff for averages
Osc R arm/Ausc L arm  Ausc R arm/Osc L arm
• Esp. elderly, DM, CKD, obese (tronco-conical arm)
Hypertension 2008; 52:13
Hypertension Res 2012; 35:777
HBPM: RECOMMENDED MONITORING PROTOCOL
Morning
Work
Evening
?
6-9 PM
 1h post-awaken
Post-micturition
---
Pre-breakfast
Pre-supper (or pre-bed?)
Pre-BP med
Pre-BP med
Rest quietly 3-5 min
Rest quietly 3-5 min
Measure X 2, 1 min apart
Measure X 2, 1 min apart
• For Dx or 2wk post-med: For 3-7 days (12-28 readings)
-  drop 1st day, average last 2-6 days
- 66% adherence!
• Stable BP period: For 3-7d, q 3-4 mo vs ongoing 3d/wk
J Hum Hypertens 2010; 24:779
Hypertension 2011; 57:9081
Hypertens Res 2012; 35:777
HBPM: NEW BP DX THRESHOLDS, 2013
AHA/ESH 2008 home BP Dx thresholds:
• Statistically-based (95th percentile) from cross-sectional
analyses
International Database of Home Blood Pressure, 2012 Dx
thresholds:
• CVD outcome-based from prospective population studies
‒ 5018 untreated patients, mean FU = 8.3y
AHA/ESH
Office BP
Home BP
IDHOCO 2012
Home BP
160/100
?
145/90
140/90
135/85
130/85
130/85
?
125/80
120/80
?
120/75
Hypertension Res 2012; 35:1072
Hypertension 2013; 61:27
HBPM: DOCUMENTATION/COMMUNICATION/ACTION
AM/PM BP X 3-7 days
Documentation: avoid
inaccurate/selected readings
Paper: Horizontal logbook
to gestalt mean BP
Device with Printer:
• Bring all print-outs
Circuit memory:
• Transfer via computer
• Record all values
Regular/Timely Communication of Data:
• Office visit, mail, FAX, computer
Action by Clinician/Team
• Dx • Rx adjustment, prn
Hypertension Res 2012; 35:777
Home BP Log: Horizontal Orientation
REDEFINE OFFICE BP MEASUREMENT:
AUTOMATED OFFICE BP (AOBP)?
3 validated devices automatically measure/average multiple BP’s:
6 readings – average last 5
BpTRU
• q 1 min: start of one  start of next
($900-1100)
3 readings – average all 3
Omron HEM-907
• q 1 min: end of one  start of next
($520)
Microlife Watch BP office
($1100)
3 readings – average all 3
• q 1 min: end of one  start of next
• Additional auscultatory mode
• Provide comparable mean readings
• Similar time to complete 6 vs 3 readings
Can J Card 2012; 28:341
J Hypertens 2012; 30:1894
REDEFINE OFFICE BP MEASUREMENT:
AUTOMATED OFFICE BP (AOBP)?
3 basic principles of AOBP:
– Fully automated device
Eliminates many technical errors
• More accurate
– Multiple measurements taken Controls for BP variability
• More reproducible
– Performed in isolation
Reduces white-coat effect
• Equivalent to daytime ABPM
Can J Card 2012; 28:341
J Hypertens 2012; 30:1894
SEQUENTIAL BpTRU READINGS IN 284
PATIENTS IN PRIMARY CARE
Reading No.
AOBP
1 (observer present)
147/82
2 (observer absent)
140/79
3
“
136/78
4
“
134/77
5
“
132/76
6
“
133/77
Mean 2-6
136/78
What does this pattern mean?
BMJ 2011; 342:d286
AOBP ON ISOLATED PATIENTS:  WHITE COAT HTN
Beckett, 2005
Routine
Office BP
BpTRU
AOBP
Daytime
ABPM
151/83
140/80
142/80
152/87
132/75
134/77
150/89
133/80
135/81
149/83
138/80
141/80
150/81
136/78
133/74
• 481 pts
Myers, 2009
 309 pts
Myers, 2010
 254 pts
*Godwin, 2011
 654 pts
*Myers, 2011
 303 pts
AOBP, isolated pt, is close to daytime ABPM: reduces WCH
* 1 care
Can J Card 2012; 28:341
Hypertension 2010; 55:195
BMJ 2011; 342:d286
Fam Pract 2011; 28:110
EQUIVALENT BPs TO DX HYPERTENSION
Routine office BP
Research quality office BP*
Daytime ABPM*
BP, mm Hg
?
 140/90
 135/85
 130/80
• 24 hour ABPM*
Home BP for 3-7 days*
AOBP, isolated patient**
 135/85 (130/85?)
 135/85?
*Supported by CVD outcome data
**Superior to routine BP for LV mass, CIMT, albuminuria but CVD outcome data
pending (CAMBO RCT)
Hypertension 2012; 11/5 epub
J Hypertens 2012; 30:1894
J Hypertens 2012; 30:1906
Am J Hypertens 2012; 25:969 Am J Hypertens 2011; 24:661
TREATMENT OF HYPERTENSION
LIFESTYLE MODIFICATION: OLD AND NEW
 BP, mm Hg
Wt loss/Kg: diet
1/1
•  4 kg: diet
6/-
•  4 kg: orlistat
2.5/-
•  4 kg: sibutramine
0/0
•  16%, 10y: bariatric surgery
 0.5/ 2.6
Exercise:
• Land-based, to 90 min/wk
5/3
-  benefit in elderly
• Swimming RCT,
45 min, 3-4d/wk, x 3 mo
9/4
Eur Heart J 2011; 32:3081
Am J Card 2012; 109:1005
LIFESTYLE MODIFICATION: OLD AND NEW
 BP, mm Hg
DASH diet RCT:
11/6
• Fruit, veggies, low fat dairy, low sat fat
Black tea RCT:
2/2
• 3 cups/d X 6 mo
Coffee:
0.5/0.5 (NS)
• 10 RCT; 5 cohort studies
Alcohol meta-analysis:
•  2 drinks/d
0/0
• 3-5 drinks/d
 3/2
Eur Heart J 2011; 32:3081
J Hypertens 2012; 30:2245
Arch Int Med 2012; 172:186
J Clin Hypertens 2012; 14:792
LIFESTYLE MODIFICATION: OLD AND NEW
Outcome
Sugar-sweetened drinks:
HTN  13%
Artificially-sweetened drinks:
HTN  14%
• 3 prospective cohorts, 223,891 pts
Vitamin D:
• 2 meta-analyses
No BP effect
• RCT, winter months
RCT, blacks
 4/3 if Vit D < 32 ng/ml
 4/2
Dark Chocolate:
• RCT, 6.3 g, 30 cal/d
 3/2
• RCT, 100 g, 500 cal/d
 5/3
Hypertension 2013; 61:779
J Gen Int Med 2012; 27:1197
Am J Hypertens 2012; 25:1215
Eur Heart J 2011; 32:3081
Am J Hypertens 2012; 23:97
LIFESTYLE MODIFICATION 2012; “SALT WARS”
 Dietary Na < 1500 – 2300 mg/d (IOM, DHSS, AHA 2012)
Benefits
 Na intake 1.2-2.4 g/d
 SBP:
HTN: 4-7 mm Hg
NT: 2.5-3.5 mm Hg
?? Adverse effects
renin,  aldosterone
 catecholamines
 triglycerides
 insulin resistance (?)
(esp. if abrupt, severe, or DM)
Potentially prevent 11 million
HTN cases
 Dietary Na   CVD?
• 2011-2012: 6 risk association studies
2  Benefits; 2  Harm; 2  J-curve
• 2011-2012: 3 meta-analyses
1  Benefit 1  No benefit 1  J-curve
NEJM 2013; 368:1229
Am J Med 2012; 125:443
Circulation 2012; 126:2880
Am J Hypertens 2012; 25:727
“SALT WARS”: THE SCIENTIFIC RESPONSE
AHA Presidential Advisory, Dec 2012: “The evidence base
supporting recommendations for reduced sodium intake to <
1500 mg/d in the general population remains robust and
persuasive.”
British Hypertension Society, July 2011: “The benefits of salt
reduction are clear and consistent.”
Reviewer commentary, AJH, Jan 2012: “Community sodium
reduction: is it worth the effort?... A concerted campaign to
reduce obesity and alcohol intake may be more rewarding and
less risky.”
Reviewer commentary, AJH, Jan 2012: “The solution to the
debate is the conduct of a large-scale, long-term clinical trial.”
“SALT WARS”: THE MEDIA/INDUSTRY RESPONSE
NY Times, June 2012: “Now, salt is safe to eat.”
London Daily Express, July 2011: “Now salt is safe to
eat – Health fascists proved wrong after lecturing us all
those years.”
Forbes.com, June 2011: “Campbell Soup increases
sodium as new studies vindicate salt.”
EDUCATION TOOLS FOR LIFESTYLE MODIFICATION
Low diet Na/DASH diet: Canadian HTN Education
Program
www.hypertension.ca/images/2012_HealthyEatingFor
HealthyBloodPressure_EN_P1017.pdf
www.sodium101.ca
DASH diet:
www.dashdiet.org
www.mayoclinic.com/health/dash-diet/H100047
In Spanish:
www.wellnessproposals.com/nutrition/handouts/dashdiet/DASH-diet-eating-plan-spanish-version.pdf
OPTIMAL 1st DRUG RX FOR HTN?
RECOMMENDATIONS FROM RECENT GUIDELINES
Preferred
Acceptable
ACE-I
ARB
• Esp. age < 55, white • Concern with 
─ ↓ BP
MI protection in
2011/2012
Thiazides
meta-analyses
• Esp. age > 65, or blacks
─ ↓ BP
• Chlorthalidone?
─ ↓ BP
CCB
Can J Card 2012; 28:270
J Gen Int Med 2012; 27:618
Less Useful
Alpha-blockers
•  HF, stroke
protection
Beta-blockers
•  stroke, MI
protection age > 60
DRI (aliskiren)
•  stroke in
ALTITUDE
BMJ 2011; 343:d4891 www.heartfoundation.org.au
BMJ 2011; 342;d2234 Eur Heart J 2012; 33:2088
JAMA 2012; 208:1340
BMJ 2009; 338:b1665
HCTZ vs CHLORTHALIDONE:
CHOICE GIVEN MOSTLY INDIRECT EVIDENCE?
Efficacy to lower BP:
• Meta-analysis: 26 RCTs; 4683 pts
Dose to  SBP 10 mm Hg
HCTZ
26.4 mg
CTDN
8.6 mg
(Similar BP reduction at maximal doses)
• RCT: 609 pts on azilsartan 40 mg  12.5-25 mg thiazide
SBP: CTDN-HCTZ = 5.6 mm Hg, p < 0.001
HTN control < 140/90 = 64% vs 46%, p < 0.001
Hypertension 2012; 59:1104
Am J Med 2012; 125:1229.e1
HCTZ vs CHLORTHALIDONE:
CHOICE GIVEN MOSTLY INDIRECT EVIDENCE?
Efficacy to reduce CVD events: indirect comparisons
Risk Reduction
CTDN vs HCTZ
Network meta-analysis:
• 3 HCTZ RCTs;
6 CTDN RCTs
MRFIT post-hoc analysis
Observational Cohort
 21%
p value
< 0.0001
 21%
 7%
0.002
NS
( Hosp. for  K,  Na)
Ann Int Med 2013; 158:447
Hypertension 2012; 59:1110
Hypertension 2011; 57:689
HCTZ vs CHLORTHALIDONE:
CHOICE GIVEN MOSTLY INDIRECT EVIDENCE?
Practical utility:
• Availability:
CTDN less available in retail pharmacies
• Preparation:
HCTZ: 12.5 mg, 25 mg tabs
CTDN: unscored 25, 50 mg tabs
• Fixed-dose combinations:
HCTZ: 19 at 12.5 and 25 mg doses
CTDN: 3 (azilsartan ($90/mo), atenolol, clonidine)
INITIAL 2-DRUG vs DELAYED 2-DRUG Rx
Rationale:
•  75% need  2 drugs, 30% need  3 drugs
‒ Especially if BP  160/100, obese, CKD, DM
• Low-dose 2-drug vs High dose 1 drug:
‒ Greater SBP reduction (3-4 mm Hg)
‒ Fewer side effects
Benefits in studies:
•  year 1 HTN control rates 20-50% (RCTs, cohorts)
•  year 1 CVD events 11-34% (cohort, case-control studies)
•  health care costs 10%
Caution: frail elderly, baseline orthostatic BP 
Hypertension 2012; 59:1124
Hypertension 2013; 61 (Feb)
Curr Opin Neph Hypertens 2012; 21:486
OPTIMAL 2-DRUG RX FOR HTN?
AMERICAN SOCIETY OF HYPERTENSION, 2010*
Preferred
Acceptable
Less Acceptable
ACE-I (ARB)/CCB
CCB/D
ACE-I/ARB
• ACCOMPLISH
RCT: 2008, 2010
ACE-I (ARB)/D
• Esp. AAs
BB/D
•  DM
BB/DHP-CCB
*Based on  BP, side
effects, or CVD-CKD
outcomes
Dual CCB
DRI/D or CCB
• No  CVD, little
 BP,  side effects
ACE-I (ARB)/BB
• Little  BP
DRI/ACE-I (ARB)
•  stroke in
ALTITUDE
BB/Clonidine or
non-DHP-CCB
• Bradycardia
J Am Soc HTN 2010; 4:42
Eur Heart J 2011; 32:2499
ACE-I/CCB vs ACE-I/DIURETIC?
ACCOMPLISH, 2008: 11,056 high CVD risk patients x 36 mo
Benazepril/Amlodipine
vs
Benazepril/HCTZ
 Others
CVD events
CKD events
 Others
ACE-I/CCB
ACE-I/D
HR
CI
9.6%
2.0%
11.8%
3.7%
0.80
0.52
0.72-0.90
0.41-0.65
• 2X  Cr
• Dialysis
• No difference in CVD events in obese
• No difference in CKD events in AAs
Kid Int 2012; 81:568
ASH, 2012 abst.
NEJM 2008; 359:2417
Lancet 2010; 375:1173
PREFERRED 3-DRUG HTN RX?
EXPERT CONSENSUS ONLY
• Diuretic/ACE-I (ARB)/CCB
• Diuretic/BB/DHP-CCB
• ACE-I/CCB/alpha-blocker (ASCOT RCT)
Can J Card 2012; 28:270
 1 HTN DRUG AT BEDTIME: CHRONOTHERAPY?
2 RCTs: 448 pts, T2DM  HTN
661 pts, CKD  HTN
5.4y
All HTN meds AM
5.4y
 1 HTN med HS
•  nocturnal BP but same daytime BP
•  CVD events with  1 HTN med HS:
‒ T2DM:  75% for CVD death  MI  stroke
‒ CKD:  71% for CVD death  MI  stroke
ADA 2013 Standard of Care: give  1 HTN med HS
• Need more studies!
J Am Soc Neph 2011; 22:2313
Diabetes Care 2011; 34:1270
Diabetes Care 2013; 36:(Suppl 1):S11
RESISTANT HYPERTENSION
Definition:
– BP  140/90 x 3 mo on  3 meds (diuretic  optimal dosing)
Prevalence:
– Increasing in NHANES – 16 million Americans
1994
2004
2008
8.8%
14.5%
20.7%
Risk factors:
– Age  75, obesity, CKD, DM,  SBP, blacks/Hispanics
Prognosis:
– 50%  CVD/CKD events in 1st 4y (Kaiser Permanente)
Circulation 2012; 125:1594, 1635
Hypertension 2011; 57:1045, 1076
Circulation 2011; 124:1046
Curr Opin Card 2012; 27:386
SUSPECT RESISTANT HTN:
• BP ≥ 140/90 (AOBP ≥ 135/85) x 3 mo – accurately measured
• ≥ 3 medications: optimal dosing  diuretic

RULE-OUT PSEUDO-RESISTANT HTN:
 for non-compressible arteries: RFs  orthostatic symptoms
 for white-coat resistant HTN: 24h ABPM or HBPM
 for optimal 3 drug Rx: CCB  ACE-I (ARB)  diuretic  eGFR
 for low Rx adherence to medication

CONSIDER ( EVALUATE) 2 CAUSES OF HTN

INTENSIFY LIFESTYLE RX:  DIET Na   EXERCISE

ADD APPROPRIATE STEP 4/5 MEDICATIONS
RULE-OUT PSEUDO-RESISTANT HTN
 for non-compressible arteries:
• RFs:  age, ESRD, DM calcific AS, scleroderma
• Orthostatic dizziness despite  standing BP
Clinical suspicion high
Intra-arterial BP measurement
J Hum Hypertens 1997; 11:285
Blood Press Monit 2003; 8:97
RULE-OUT PSEUDO-RESISTANT HTN
 for White-coat resistant HTN: 24h ABPM or HBPM
Study
# Patients
% White-Coat RH
Redon, 1998
86
33%
Brown, 2001
118
28%
Pierdomenico, 2005
276
49%
Hermida, 2005
700
17%
Oikawa, 2006
528
16%
Salles, 2008
556
37%
Douma, 2008
2302
29%
De la Sierra, 2011
8295
38%
• 1/3 with office RH have white-coat RH!
Nat Rev Nephrol 2013; 9:51
RULE-OUT PSEUDO-RESISTANT HTN
for optimal 3-drug Rx – maximal tolerated doses of:
• CCB  ACE-I (ARB)  diuretic  eGFR
 eGFR
< 30 ml/min
≥ 30 ml/min
 total body Na
Furosemide/bumetanide bid (8AM, 5PM)
Chlorthalidone 25 mg/d
or
Torsemide qd
Titrate dose to 4-5 lb wt loss only
*22% not on diuretic 1y after Dx of
RH in Kaiser system!
57% not maximally dosed on meds!
Monitor creatinine/potassium carefully
Eur Heart J 2013; on-line 2/5, Messerli
BMJ 2012; 345:e7473
Hypertension 2012; 60:303
RULE-OUT PSEUDO-RESISTANT HTN
 for low Rx adherence to medication:
“Drugs don’t work in people who don’t take them.”
C.E. Koop, M.D.
• Ask the patient: occurs in only 30% of visits with  BP
• Pharmacy refill rates: < 80% possession ratio
• Epidemiologic clues: young, male, non-white, depression,
> qd dosing, branded meds, side-effect worries
• Difficult to confirm objectively:
Toxicologic urine screening in
RH pts in Germany  37% non-adherent
J Hypertension 2013; 31:766
TRUE RESISTANT HTN: CONSIDER 2 ETIOLOGIES
Drugs that  BP
Primary
Aldosteronism
Renovascular
HTN
OSA
• NSAIDS:  SBP  5 mm Hg, ≥ 10 mm Hg in 10%
• OCPs: age ≥ 35, obese, smoke, AA
• Epogens: in 20%,   Hct
• Corticosteroids: in 15-20%
• Calcineurin inhibitors: cyclosporine, tacrolimus
• Antiangiogenic cancer Rx agents
• Stimulant/anorexic drugs for ADD, wt loss
• Herbals: ephedra, ginseng, bitter orange
• ETOH > 4 drinks/d, cocaine, amphetamines
J Clin Hypertens 2008; 10:556
Am Heart J 2013; 165:477
TRUE RESISTANT HTN: CONSIDER 2 ETIOLOGIES
Drugs that  BP
Primary
Aldosteronism
Renovascular
HTN
OSA
• 10-20% of RH pts
• < 40% have  K+
• Aldosterone: independent CV toxin
- 3-6X more CVD than essential HTN
• AHA, 2008: screen all RH patients
- Spironolactone Rx for all to  CVD
- Evaluate a few for adenoma – adrenal vein cath
Hypertension 2008; 51:1403
J Clin Endo Metab 2008; 93:3266
PRIMARY ALDOSTERONISM: EVALUATION
Aldosterone/Renin Ratio (ARR): AM sitting blood draw
• No K+ - sparing diuretic x 4 wks • Normokalemic
ARR < 20
No PA
ARR ≥ 20
3d Na oral loading, 200 mEq/d
• Early AM PRA
• 24h urine: aldosterone, Na, creatinine
PRA < 1.0 ug/ml/h and urine aldosterone ≥ 12 ug/d and urine Na > 200 mEq
No
Yes
PA
Spironolactone Rx
vs
Surgical evaluation:
CT  adrenal vein cath
Hypertension 2008; 51:1403
TRUE RESISTANT HTN: CONSIDER 2 ETIOLOGIES
Drugs that  BP
Primary
Aldosteronism
Renovascular
HTN
OSA
Fibromuscular Dysplasia Atherosclerotic RAS
Women  age 50y
Refractory HTN
with RH

Progressive  eGFR,
spontaneous or if Rx
Screen with MRA/CTA
• 50% curable
• 30% improved
or
Recurrent HF
Screen with MRA/CTA/US
• Uncertain benefits
Kidney International 2012; 83:28
- Θ in ASTRAL, STAR
- CORAL pends
TRUE RESISTANT HTN: CONSIDER 2 ETIOLOGIES
Drugs that
Primary
Renovascular
Aldosteronism
HTN
 BP
OSA
• Prevalence in RH: 71-85%
(vs 38-55% in non-RH)
• CPAP efficacy to  SBP:
- Non-RH: 1.6-2.5 mm Hg
(4 meta-analyses)
- RH: 7-9 mm Hg??
(small observational studies)
J Hypertension 2012; 30:633
MEDIATORS OF RH: ALDOSTERONE/VOLUME
Gaddam, 2008; 249 RH pts vs 53 controls (controlled HTN, normal BP)
Plasma aldosterone (ng/dl)
24h urine aldosterone (ug/24h)
ARR
BNP (pg/ml)
ANP (pg/ml)
RH pts
13.0
Control pts p value
8.4
< 0.001
13.0
22
37.2
95.9
9.7
6
22.5
54.8
0.02
< 0.001
0.007
0.001
RH mediated by:
• Relative aldosterone excess
• Persistent ECF volume expansion
Arch Int Med 2008; 168:1159
INTENSIFY LIFESTYLE RX FOR RESISTANT HTN
Lower Dietary Na:
• 12 pts with RH: mean BP = 146/84 on 3 meds
Final BP
1g Na x 7d
123/75
6g Na x 7d
146/84
‒ Very low Na diet  BP 23/9 mm Hg
Aerobic Exercise:
• 50 pts with RH: mean BP = 141/78 on 4 meds
8-12 wks treadmill exercise
 BP 6/3 mm Hg
Hypertension 2009; 54:475
Hypertension 2012; 60:653
RESISTANT HTN: ALDOSTERONE BLOCKADE
# Patients
 Office BP, mm Hg
Retrospective: 2 studies
386
-25/12
Prospective obs.: 5 studies
1803
-22/10
RCT (Alvarez-Alvarez, 2010)
41
-32/11
RCT (Parthsarathy, 2011)
141
-27/12
111
-15/7
52
-18/8
Study Type
Spironolactone:
RCT (Vaclavik, 2011)
Eplerenone:
Prospective obs.:
• Spironolactone side effects: hyperkalemia (3-5%); breast tenderness (5-10%)
Ann Pharmacother 2010; 44:1762
J Hypertens 2010; 28:2329
J Hypertens 2011; 29:980
J Am Soc HTN 2010; 4:290
Hypertension 2011; 57:1069
RESISTANT HTN: 4-5 DRUG RX?
ACE-I (ARB)  DHP-CCB  Thiazide (chlorthalidone)
BP > goal
K < 4.5 and eGFR  45
HR > 84-90/min
“Sequential nephron blockade” •
Spironolactone, 12.5-25 mg/d

Beta-Blocker
(? vasodilating)
K  4.5 or eGFR < 45;
HR < 84-90
Alpha-blocker:
 BP 16/9,
obs. study
Non-DHP CCB:
 BP 10/10,
obs. study
• Furosemide, 20-40 mg/d

Beta-blocker  alpha-blocker:
Controlled 25%, obs. study
• Amiloride, 5 mg/d
RCT:  BP 18/13, controlled 58%
Device Therapy?
Rev Esp Card 2009; 62:158
J Clin Hypertens 2005; 7:50
J Clin Hypertens 2012; 14:191
Am J Hypertens 2011; 24:863
BMJ 2012; 345:e7473
J Hypertension 2012; 30:1656
J Clin Hypertens 2012; 14:191
DEVICE RX FOR RESISTANT HTN: HOPE OR HYPE?
Rationale: Inhibit Sympathetic NS
 Renal Sympathetic Overactivity:
• PTRA sympathetic nerve ablation
Activate Carotid Baroreceptors:
• CS electrical stimulators
SYMPLICITY HTN-2 RCT
Rheos Pivotal RCT
• 106 pts; mean BP = 178/96
• 265 pts; mean BP = 169/101
•  Office BP, 6 mo = 32/12
•  office BP, 12 mo: 25/-
• 19% HTN control rate
• 42% HTN control rate
• 25% minor complication rate
• FU: sustained  BP to 24 mo
• 25% complication rate –
5% permanent nerve deficit!
• FU: sustained  BP to 22 mo
CAUTION!
• Sub-optimal Rx regimens pre-enrollment
• Short duration FU on small numbers
• Based on office BP – ABPM   11/8, SYMPLICITY-2
- Suppressing primarily white-coat effect?
- SYMPLICITY HTN-3 RCT in U.S. pends
Hypertension 2012; 60:596
Lancet 2012; 380:591
J Hypertens 2012; 30:837, 874
Heart 2012; 98:1689
Interven Image 2012; 93:386