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 62% • MI 25%• CKD 56% • Premature death 24%• HF 49%

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

% BP 140/90

All 30%

• Age 60y 67%

• White 29%

• Black 42%

• Hispanic 27%

- No change in HTN prevalence since 2000• 75 million Americans have HTN

JACC 2012; 60:599

HTN CONTROL (< 140/90) RATES: 1988-2010 NHANES

1988

2001

2010

All 27% 29% 47%

• White --- 30% 50%

• Black --- 25% 41%

• Hispanic --- 25% 34%

• CVD --- --- 55%

• DM < 130/80 --- --- 42%

• CKD < 130/80 --- --- 39%

(40% M, 56% W)

Healthy People 2020 Goal

61%

---

---

---

---

---

---

Canada 2010

VA 2010

65% 76%

--- ---

--- ---

--- ---

--- ---

--- ---

--- ---

‒ 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 15% Aware, No Rx

45% Rx’d, Uncontrolled • Older, women, obese, AA, CKD, CVD, DM

• Younger, men, Hispanic, finances, 0-1 visits/y

Screening Access to care

• Work, CC’s, church

• Insurance • Availability

Media outreach

Pseudo-HTN • Control for BP variability • Measure BP accurately • Detect WCH

Rx inertia • 65% on 1-2 drugs

Rx efficiency

Pt adherence

MMWR 2012; 61:703 MMWR 2011; 60:103 Circulation 2011; 124:1046 Can J Card 2012; 28:375

HOW LOW TO GO? TARGET BP, 2013Guideline General Age 80 CKD DM

JNC-7, 2003 < 140/90 --- < 130/80 < 130/80

CHEP, 2013 < 140/90 < 150 < 140/90 < 130/80

NKF-KDIGO, 2012 --- --- <140/90if ACR <30 130/80 if ACR ≥ 30

< 140/90if ACR <30 130/80if ACR ≥ 30

NICE, 2011 < 140/90 < 150/90 --- ---

ACCF/AHA, 2011 --- 140-145* --- ---

ADA, 2013 --- --- --- < 140/80**

JNC-8, 2013 ? ? ? ?

*Initiate Rx if SBP 150 mm Hg** <130/80 in younger/↑ stroke risk pts

Can J Card 2013; online 3/25 BMJ 2011; 343:d4891 Circulation 2011; 123:2434Diabetes 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

Final SBP = 143

RRR

Total Stroke 30%

Fatal Stroke 39%

Mortality 21%

CHF 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

PlaceboIndapamide ACE-I

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

126-130/77-80

RRR

CVD events NS

CKD progression NS

Mortality NS

• Subgroup with proteinuria 300-1000 mg/d*: HR

CVD events NSCKD progression 24-39%

Ann Int Med 2011; 154:541

130-139/80-89< 130/80

*Low quality evidence

DIABETES MELLITUS: HOW LOW TO GO?Meta-analysis: 13 RCTs, mean achieved systolic BP

< 140

37,736 pts 135

130

Risk Reduction vs < 140

135 130

Total mortality 10% NS

Stroke 17% 47%

MI NS NS

ESRD/2X Cr 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 Study

# 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

Powers, 2011 444 145/- 129/- -16/-

Accurate measurement BP by 10/7 mm Hg

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 ≥ 180/110or ≥ 140/90 and CVD, DM, or CKD

R/O White-coat HTN: 20-33%

Dx HTNYes

No: BP = 140-179/90-99 and low risk

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

Home BPM x 7d • Mean BP 135/85

BP < 135/85

Dx HTNCan 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 averagesOsc 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

1h post-awaken ? 6-9 PM

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, 2013AHA/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

Office BP

AHA/ESH 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

Paper: Horizontal logbook to gestalt mean BP

Device with Printer:

• Bring all print-outs

Circuit memory: • Transfer via computer

• Record all values

Documentation: avoid inaccurate/selected readings

Regular/Timely Communication of Data: • Office visit, mail, FAX, computer

Action by Clinician/Team

• Dx • Rx adjustment, prnHypertension 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:BpTRU 6 readings – average last 5($900-1100) • q 1 min: start of one start of next

Omron HEM-907 3 readings – average all 3($520) • q 1 min: end of one start of next

Microlife Watch BP office 3 readings – average all 3($1100) • 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) 147/822 (observer absent) 140/79

3 “ 136/78 4 “ 134/77 5 “ 132/76 6 “ 133/77Mean 2-6 136/78

What does this pattern mean?

BMJ 2011; 342:d286

AOBP ON ISOLATED PATIENTS: WHITE COAT HTN

Routine Office BP

BpTRU AOBP

Daytime ABPM

Beckett, 2005 151/83 140/80 142/80

• 481 pts

Myers, 2009 152/87 132/75 134/77

309 pts

Myers, 2010 150/89 133/80 135/81

254 pts

*Godwin, 2011 149/83 138/80 141/80

654 pts

*Myers, 2011 150/81 136/78 133/74

303 pts

AOBP, isolated pt, is close to daytime ABPM: reduces WCH

Can J Card 2012; 28:341 Hypertension 2010; 55:195 BMJ 2011; 342:d286 Fam Pract 2011; 28:110

* 1 care

EQUIVALENT BPs TO DX HYPERTENSION

BP, mm Hg

Routine office BP ?

Research quality office BP* 140/90

Daytime ABPM* 135/85 • 24 hour ABPM* 130/80

Home BP for 3-7 days* 135/85 (130/85?)

AOBP, isolated patient** 135/85?

*Supported by CVD outcome data**Superior to routine BP for LV mass, CIMT, albuminuria but CVD outcome data pending (CAMBO RCT)

J Hypertens 2012; 30:1894 J Hypertens 2012; 30:1906Hypertension 2012; 11/5 epub 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 Arch Int Med 2012; 172:186J Hypertens 2012; 30:2245 J Clin Hypertens 2012; 14:792

LIFESTYLE MODIFICATION: OLD AND NEWOutcome

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

J Gen Int Med 2012; 27:1197 Eur Heart J 2011; 32:3081Hypertension 2013; 61:779 Am J Hypertens 2012; 25:1215 Am J Hypertens 2012; 23:97

LIFESTYLE MODIFICATION 2012; “SALT WARS”

Dietary Na < 1500 – 2300 mg/d (IOM, DHSS, AHA 2012)

Na intake 1.2-2.4 g/d

SBP:HTN: 4-7 mm Hg

NT: 2.5-3.5 mm Hg

Potentially prevent 11 million HTN cases

­renin, aldosterone catecholamines triglycerides insulin resistance (?)(esp. if abrupt, severe, or DM)

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-curveNEJM 2013; 368:1229 Circulation 2012; 126:2880

Am J Med 2012; 125:443 Am J Hypertens 2012; 25:727

Benefits ?? Adverse effects

“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/dash-diet/DASH-diet-eating-plan-spanish-version.pdf

OPTIMAL 1st DRUG RX FOR HTN? RECOMMENDATIONS FROM RECENT GUIDELINES

Preferred

ACE-I

• Esp. age < 55, white─ ↓ BP

Thiazides

• Esp. age > 65, or blacks─ ↓ BP

•Chlorthalidone?─ ↓ BP

CCB

Acceptable

ARB

• Concern with MI protection in 2011/2012 meta-analyses

Less Useful

Alpha-blockers

• HF, stroke protection

Beta-blockers

• stroke, MI protection age > 60

DRI (aliskiren)

• stroke in ALTITUDE

Can J Card 2012; 28:270 BMJ 2011; 343:d4891 www.heartfoundation.org.auJ Gen Int Med 2012; 27:618 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 comparisonsRisk Reduction CTDN vs HCTZ

p

value

Network meta-analysis: 21% < 0.0001

• 3 HCTZ RCTs;

6 CTDN RCTs

MRFIT post-hoc analysis 21% 0.002

Observational Cohort 7% 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

ACE-I (ARB)/CCB

• ACCOMPLISH RCT: 2008, 2010

ACE-I (ARB)/D

*Based on BP, side effects, or CVD-CKD outcomes

Acceptable

CCB/D

• Esp. AAs

BB/D

• DM

BB/DHP-CCB

Dual CCB

DRI/D or CCB

Less Acceptable

ACE-I/ARB

• 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 OthersACE-I/CCB ACE-I/D HR CI

CVD events 9.6% 11.8% 0.80 0.72-0.90

CKD events 2.0% 3.7% 0.52 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?

• 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

2 RCTs: 448 pts, T2DM HTN 661 pts, CKD HTN

All HTN meds AM

1 HTN med HS

5.4y

5.4y

RESISTANT HYPERTENSION

Definition:– BP 140/90 x 3 mo on 3 meds (diuretic optimal dosing)

Prevalence:– Increasing in NHANES – 16 million Americans

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 Circulation 2011; 124:1046

Hypertension 2011; 57:1045, 1076 Curr Opin Card 2012; 27:386

1994 2004 2008

8.8% 14.5% 20.7%

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

Intra-arterial BP measurement

J Hum Hypertens 1997; 11:285 Blood Press Monit 2003; 8:97

Clinical suspicion high

RULE-OUT PSEUDO-RESISTANT HTN for White-coat resistant HTN: 24h ABPM or HBPMStudy # Patients % White-Coat RHRedon, 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

Furosemide/bumetanide bid (8AM, 5PM) Chlorthalidone 25 mg/d

or

Torsemide qd

Titrate dose to 4-5 lb wt loss only

Monitor creatinine/potassium carefully

*22% not on diuretic 1y after Dx of RH in Kaiser system! 57% not maximally dosed on meds!

≥ 30 ml/min< 30 ml/min

total body Na

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

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

PASpironolactone Rx vs Surgical evaluation:

CT adrenal vein cath

No PA

ARR < 20ARR ≥ 20

NoYes

Hypertension 2008; 51:1403

TRUE RESISTANT HTN: CONSIDER 2 ETIOLOGIES

Drugs that BP Primary Aldosteronism

Renovascular HTN

OSA

Women age 50y Refractory HTN

with RH

Progressive eGFR, spontaneous or if Rx

Screen with MRA/CTA or

• 50% curable • 30% improved

Recurrent HF

Screen with MRA/CTA/US

• Uncertain benefits - Θ in ASTRAL, STAR - CORAL pends

Fibromuscular Dysplasia Atherosclerotic RAS

Kidney International 2012; 83:28

TRUE RESISTANT HTN: CONSIDER 2 ETIOLOGIES

Drugs that BP

Primary Aldosteronism

Renovascular

HTN

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

RH pts Control pts p value

Plasma aldosterone (ng/dl) 13.0 8.4 < 0.001

24h urine aldosterone (ug/24h) 13.0 9.7 0.02

ARR 22 6 < 0.001

BNP (pg/ml) 37.2 22.5 0.007

ANP (pg/ml) 95.9 54.8 0.001

Gaddam, 2008; 249 RH pts vs 53 controls (controlled HTN, normal BP)

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

‒ Very low Na diet BP 23/9 mm Hg

Aerobic Exercise:• 50 pts with RH: mean BP = 141/78 on 4 meds

1g Na x 7d 6g Na x 7d

Final BP 123/75 146/84

8-12 wks treadmill exercise

BP 6/3 mm Hg

Hypertension 2009; 54:475 Hypertension 2012; 60:653

RESISTANT HTN: ALDOSTERONE BLOCKADE

Study Type # Patients Office BP, mm Hg

Spironolactone:

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

RCT (Vaclavik, 2011) 111 -15/7

Eplerenone:

Prospective obs.: 52 -18/8

• Spironolactone side effects: hyperkalemia (3-5%); breast tenderness (5-10%)

Ann Pharmacother 2010; 44:1762 J Hypertens 2010; 28:2329 J Am Soc HTN 2010; 4:290J Hypertens 2011; 29:980 Hypertension 2011; 57:1069

RESISTANT HTN: 4-5 DRUG RX?

ACE-I (ARB) DHP-CCB Thiazide (chlorthalidone)

K < 4.5 and eGFR 45 HR > 84-90/min K 4.5 or eGFR < 45; HR < 84-90

“Sequential nephron blockade” • Spironolactone, 12.5-25 mg/d

Beta-Blocker (? vasodilating)

Alpha-blocker: BP 16/9, obs. study

Non-DHP CCB: BP 10/10, obs. study

• Furosemide, 20-40 mg/d

• Amiloride, 5 mg/d Beta-blocker alpha-blocker: Controlled 25%, obs. study

RCT: BP 18/13, controlled 58%

Device Therapy?

Rev Esp Card 2009; 62:158 J Clin Hypertens 2005; 7:50 Am J Hypertens 2011; 24:863 J Hypertension 2012; 30:1656J Clin Hypertens 2012; 14:191 BMJ 2012; 345:e7473 J Clin Hypertens 2012; 14:191

BP > goal

DEVICE RX FOR RESISTANT HTN: HOPE OR HYPE?Rationale: Inhibit Sympathetic NS

Renal Sympathetic Overactivity: Activate Carotid Baroreceptors:

• PTRA sympathetic nerve ablation • 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

• 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 Heart 2012; 98:1689J Hypertens 2012; 30:837, 874 Interven Image 2012; 93:386

CAUTION!