jnc 8 & conquering hard-to-treat hypertension files/spring 2014 syllabu… · 1 session 6...

JNC 8 & Conquering Hard-to-Treat Hypertension

Regional Conference New York, New York

May 28, 2014

Content Collaborator

Session 6

Session 6: JNC 8 & Conquering Hard-to-Treat Hypertension Learning Objectives 1. Analyze the new hypertension guidelines. 2. Compare and contrast different hypertension guidelines. 3. Evaluate lifestyle modification and medical therapies for the treatment of hypertension. 4. Describe new interventional options to treat resistant hypertension.

Faculty Karol E. Watson MD, PhD, FACC Associate Professor of Medicine Division of Cardiology Director, UCLA Center for Cholesterol and Hypertension Management Director, UCLA Women's Cardiovascular Center David Geffen School of Medicine University of California Los Angeles, California Dr Karol Watson is an associate professor of medicine and codirector lipid clinic at UCLA Medical Center. Dr Watson attended Harvard Medical School, completed a residency program at the University of California, and received postgraduate training in cardiology at UCLA. She is board certified in the areas of tnternal medicine and cardiology. Dr Watson has published articles in various scientific journals, including Arteriosclerosis, Thrombosis, and Vascular Biology and Circulation. In addition, Dr Watson also serves as a reviewer for Arteriosclerosis, Thrombosis, and Vascular Biology. She is chair of the cholesterol committee of the Association of Black Cardiologists. Faculty Financial Disclosure Statement The presenting faculty reports the following: Karol E. Watson MD, PhD has received consulting fees from Merck & Co., Inc.

1

SESSION 64–5pm

JNC 8 & Conquering Hard-to-Treat Hypertension

SPEAKERKarol E. Watson MD, PhD, FACC

Presenter Disclosure Information

►Karol E. Watson MD, PhD, as a member of their Clinical Trials Adjudication Committee, has received consulting fees from Merck & Co., Inc.

The following relationships exist related to this presentation:

Off-Label/Investigational Discussion

►In accordance with pmiCME policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.

JNC 8&

Conquering Hard to Treat Hypertension

Karol E. Watson, MD, PhD, FACC

Associate Professor of Medicine /Cardiology

Co-director, UCLA Program in Preventive Cardiology

DISCLOSURES: Clinical Trials Adjudication Committee - MerckGrant funding: NIH, NIDDK

Learning Objectives

• Analyze the new hypertension guidelines.

• Compare and contrast different hypertension guidelines.

• Evaluate lifestyle modification and medical therapies for the treatment of hypertension.

• Describe new interventional options to treat resistant hypertension.

Historical Comments on Hypertension

“People with mild benign hypertension with levels up to 210/110 need not be treated”

Friedberg. Diseases of the Heart-1946

“Hypertension may be an important compensatory mechanism which should not be tampered with, even were it certain that we could control it.”

Paul Dudley White, 1931

“The greatest danger to a man with high blood pressure lies in its discovery,because then some fool is certain to try and reduce it.”Hay, Brit Med J, 1931

Historical Lessons on the Risks of Hypertension and the Benefits of Treatment

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00

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Cu

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The Framingham Study The Vet. Adm. Study II

Ann Intern Med. 1961; 55:33–50. JAMA. 1970; 213:1143–1152.

Hypertension IncreasesMorbidity and Mortality

Treatment DecreasesMorbidity and Mortality

0

20

40

60

80

100

120

140

Men Women

NormotensionHypertension

2

Even if you make it to age 65 without HTN, you’ll likely develop it

Vasan RS et al. JAMA. 2002;287:1003-1010.

100

60

20

0

80

40

Risk of hypertension

(%)

age

Men

65 77 8567 8169 71 73 75 79 83

Women

2014 Evidence-Based Guideline for the Management of High Blood

Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee

(JNC 8)

JAMA. Published online December 18, 2013. doi:10.1001/jama.2013.284427

Important to Note… JNC 7 was “The Seventh Report of the Joint National

Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure”

JNC 8 is the “2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults”

In JNC 8 they give 9 Evidence based Recommendations

“… these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient.”

• RCTs• conducted 1966 to present

• Minimum 1-year follow-up period• Sample size > 100

Strength of RecommendationGrade

AStrong recommendation: There is high certainty based on evidence that the net benefit is substantial.

BModerate recommendation: There is moderate to high certainty based on evidence that the net benefit is moderate to substantial

C Weak recommendation: There is at least moderate certainty based on evidence that there is a small net benefit.

D Recommendation against: There is at least moderate certainty based on evidence that it has no net benefit or that risks/harms outweigh benefits.

E

Expert opinion (“There is insufficient evidence or evidence is unclear or conflicting, but this is what the Panel recommends.”) Net benefit is unclear. Balance of benefits and harms cannot be determined because of no evidence, insufficient evidence, unclear evidence, or conflicting evidence, but the Panel thought it was important to provide clinical guidance and make a recommendation. Further research is recommended in this area.

N

No recommendation for or against (“There is insufficient evidence or evidence is unclear or conflicting.”) Net benefit is unclear. Balance of benefits and harms cannot be determined because of no evidence, insufficient evidence, unclear evidence, or conflicting evidence, and the Panel thought no recommendation should be made. Further research is recommended in this area.

2

3

1

0

5

0

Recommendation #1

1. In patients aged ≥60 years, initiate pharmacologic treatment in systolic BP ≥150mmHg or diastolic BP ≥90mmHg and treat to a goal systolic BP <150mmHg and goal diastolic BP <90mmHg.

(Strong Recommendation – Grade A)

In other words:Ease up on Hypertension

Treatment in Older Adults (60 years of age or older)

BP goal <150/90

HYVET Trial: Study Design

Primary Endpoint: fatal and non-fatal strokes

Secondary Endpoints: death from: stroke, cardiovascular

causes, cardiac causes and any cause

Active Treatment1.5 mg Indapamide SR (±

perindopril)

n=1933

Placebo Matching Dose

n=1912

Prospective. Randomized. Double Blind. Placebo-Controlled. Mean follow-up 1.8yrs3845 patients > 80 years with HTN and systolic blood pressure ≥ 160 mm Hg

Inclusion Criteria: Exclusion Criteria:Aged 80 or more, Standing SBP < 140mmHgSystolic BP; 160 -199mmHg Stroke in last 6 months+ diastolic BP; <110 mmHg, Dementia; Need for daily nursing care

N Engl J Med 2008;358/ACC 2008

R

Target blood pressure

150/80 mmHg

3

2014 HTN

(JNC 8)

2014

ASH/ISH

2013

CHEP

2013

ESH/ESC

2013

ADA

General BP goal 140/90 140/90 140/90 140/90 140/80

BP goal (elderly) 150/90

(60 yrs)

150/90

(80 yrs)

150/90

(80 yrs)

150/90

(80 yrs) ---

BP Tx - Blacks CCB or thiazide

CCB or thiazide

--- --- ---

BP goal CKD 140/90 140/90130/90*

140/90130/90*

140/90

BP goal DM 140/90 140/80

Initial drug choice for most

Thiazide

ACE / ARB

CCB

ACE / ARB

If < 60

CCB or thiazide if >60

Thiazide

ACE / ARB

ΒΒ

Thiazide

ACE / ARB

CCB, ΒΒ

ACE / ARB

* With proteinuria

How the Guidelines Compare… Recommendations #2 and #32. In patients aged <60 years, initiate pharmacologic

treatment at DIASTOLIC BP ≥90mmHg and treat to a goal <90mmHg.

For ages 30–59 years, Strong Recommendation–Grade AFor ages 18–29 years, Expert Opinion–Grade E

3. In patients aged <60 years, initiate pharmacologic treatment at SYSTOLIC BP ≥140mmHg and treat to a goal <140mmHg.

Expert Opinion–Grade E

For Adults under 60 years of ageBP goal <140/90

There’s strong evidence for treating high diastolic BP in patients 30-59 years of age. Everything else is “Expert

Opinion”

What???? You mean treating SBP > 140 mm Hg is only “Expert Opinion”

Prior guidelines relied on epidemiologic evidence and observational studies that noted that the risks for cardiovascular events in untreated adults increased rapidly as SBP increased above 140 mm Hg

Most older trials actually used a DBP goal rather than a SBP goal

Older trials that did target to a SBP goal, used < 160

So, direct RCT evidence to support a SBP goal < 140 is limited.

JNC 8 acknowledges this limitation

Recommendations # 4 & 5

4. In patients aged ≥18 years with chronic kidney disease, initiate pharmacologic treatment at systolic BP ≥140mmHg or diastolic BP ≥90mmHg and treat to goal systolic BP <140mmHg and goal diastolic BP <90mmHg. (Expert Opinion–Grade E)

Earlier HTN guidelines lowered treatment goals for adults with CKD and DM; but JNC 8 gives the same BP goals in these patients as in the general population.

BP goal <140/90

5. diabetes mellitus

Hypertension in CKD

The Modification of Diet in Renal Disease (MDRD) Trial 1994• N=884 pt with GFR 13-55• Randomized to a MAP < 93 (120/80) vs MAP < 107

(140/90)• RESULT: No benefit on CV or renal outcomes

AASK 2002• N=1094 African American pts with hypertensive

nephropathy t with GFR 13-55• Randomized to a MAP < 93 (120/80) vs MAP 102- 107

(130-140/90)• RESULT: No benefit on CV or renal outcomesKlahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L et. al. N Engl J Med 330:887–884, 1994Wright JT Jr et. al. Arch Intern Med. 2002;162:1636-1643

Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial NHLBI 10,251 Type 2 diabetics

Three Trial arms

• Glycemic control

• BP

• Lipids

BP arm 4,773 randomized to SBP<120 or <140

The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010 Mar 14

Hypertension in Diabetes

4

Primary Outcome Nonfatal MI, Nonfatal Stroke or CVD Death

Total Stroke

HR = 0.8895% CI (0.73-1.06)

HR = 0.5995% CI (0.39-0.89)NNT for 5 years = 89

ACCORD Trial: Outcomes


Intensive

N (%)

Standard

N (%)P

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) 0.10

Bradycardia 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) 0.12

eGFR 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 Trial: Adverse Events


Recommendations #6

6. In the general nonblack population, including those with diabetes, initial antihypertensive treatment should include a thiazide-type diuretic, CCB, ACE inhibitor, or ARB. (Moderate Recommendation–Grade B) This recommendation is different from the JNC 7 in which the panel recommended thiazide-type diuretics as initial therapy for most patients.

While JNC 7 recommended thiazide-type diuretics as the initial antihypertensive

choice for all, JNC 8 broadens the choices to also include CCB, ACE-I, and ARBs

NOTE: ßblockers are OUT

90% previously treated10% untreated

42,418 high-riskhypertensive patients

Chlorthalidone12.5-25 mg

Amlodipine2.5-10 mg

Lisinopril10-40 mg

Doxazosin1-8 mg

N=15,255 N=9,048 N=9,054 N=9,061

Hypertension Trial

STEP 1 AGENTS (Double-blind)

Step 1 agents titrated and atenolol, clonidine, reserpine, and/or hydralazine added as needed to achieve BP goal

ALLHAT

JAMA 2002; 288: 2981-2997

Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group

RR (95% CI) p value

A/C 0.98 (0.90-1.07) 0.65

L/C 0.99 (0.91-1.08) 0.81

ALLHAT

ChlorthalidoneAmlodipineLisinopril

Years to CHD Event0 1 2 3 4 5 6 7

Cum

ulat

ive

CH

D E

vent

Rat

e

0

.04

.08

.12

.16

.2

JAMA 2002; 288: 2981-2997Psaty BM, et al. JAMA. 2003;289:2534-2544.

OutcomeRelative Risk

(95% CI)P

Value

CHD 0.87 (0.74-1.03) 0.10

CHF 0.83 (0.68-1.01) 0.07

Stroke 0.90 (0.76-1.06) 0.20

CVD Events 0.89 (0.80-0.98) 0.02

CVD Mortality 0.93 (0.81-1.07) 0.34

Total Mortality 0.99 (0.91-1.07) 0.73

FavorsDiuretics

Favors-Blockers

Comparison of Diuretics and Blockers and Their Effects on CV Events

Relative Risk

0.6 0.8 1.0 1.2 1.40.4

5

Recommendation #77. In the general black population, including those with

diabetes, initial antihypertensive treatment should include a thiazide-type diuretic or CCB.

For general black population Moderate Recommendation -Grade B

For black patients with diabetes: Weak Recommendation–Grade C)

JNC 8 recommends a thiazide-type diuretic or CCB as the initial choice in

Blacks, but we’re less certain about Blacks with diabetes due to lack of data (they were

torn about not including ACE/ARB) 130

135

140

145

150

0 1 2 3 4 5 6

mm

Hg

SB

P

Years

Black subjects

Chlorthalidone

Black subjects

Amlodipine

Black subjects

Lisinopril

BP Results by Treatment Group in Black ParticipantsALLHAT

Wright JT, Dunn JK, Cutler JA et al. JAMA 2005:293:1595-1608.

Recommendation # 88. In the population aged ≥18 years with chronic kidney

disease, initial (or add-on) antihypertensive treatment should include an ACE inhibitor or ARB to improve kidney outcomes. (Moderate Recommendation–Grade B)

In adult patients with CKD, make sure an ACE-I or an ARB is part of the

antihypertensive regimen

ACE-I or ARB in CKD reduces progression of kidney disease

Study Pts Design RR for kidney disease progression

Maschio et al 1996 583 Benazapril v. placebo 53%

Gisen group 1997 166 Ramapril v. placebo 48%

Hou et al 2006 224 Benazapril v placebo 43%

Brenner et al 2001 1513 Losartan v. placebo 22%

Recommendation # 99. If goal BP is not reached within a month of treatment,

increase the dose of the initial drug or add a second drug from one of the classes in Recommendation 6. If goal BP cannot be reached with two drugs, add and titrate a third drug from the list provided. Do not use an ACEI and an ARB together in the same patient. If goal BP cannot be reached using only the drugs in Recommendation 6 … antihypertensive drugs from other classes can be used. (Expert Opinion–Grade E)

Thiazide-type diuretic, CCB, ACE-I or ARB

Don’t dilly dally. If BP is not at goal within a month, use one of these 3 strategies :

1. Increase the dose of the initial drug2. Add a 2nd, then a 3rd drug (Rec #6)

(Not an ACE + ARB together)3. Add a drug from other classes

Telmisartan vs. Telmisartan + Ramipril: Primary Outcome (MI, Stroke, CV death, CV

hospitalization)

ONTARGET

Follow-up (yrs)

Cum

ulat

ive

Haz

ard

Rat

es

0.0

0.05

0.10

0.15

0.20

0.25

0 1 2 3 4

The ONTARGET Investigators N ENGL J MED 2008; 358:1547-1559April 10, 2008

Ramipril + TelmisartanTelmisartan

6

Adverse Events with Ramipril + Telmisartan

Ram

N=8576

Ram + Tel

N=8502 RR P

Hypotension 149 406 2.75 <0.0001

Syncope 15 29 1.95 0.032

Cough 360 392 1.10 0.1885

Diarrhea 12 39 3.28 0.0001

Angioedema 25 18 0.73 0.30

Renal Impairment

60 94 1.58 0.0050

Any Discontinuation

2099 2495 1.20 <0.0001

The ONTARGET Investigators N ENGL J MED 2008; 358:1547-1559April 10, 2008

ONTARGET

Adult (age > 18 years)

Lifestyle Interventions to be applied throughout Treatment Algorithm

Set Blood Pressure Goal and Initiate Blood Pressure Lowering Medications

All ages w CKD All ages w Diabetes Age < 60 yearsAge > 60 years

Blood Pressure Goal<150 / 90 mm Hg




NON-BLACK BLACKInitiate Thiazide-type diuretic, or ACEI or ARB or CCB alone or in combination

Initiate Thiazide-type diuretic, or CCB alone or in combination

Initiate ACEI or ARBalone or in combinationwith other drug classes

ALL RACES

Select a drug titration strategyA. Maximize first drug B. Add second drug before reaching max of first C. Start with 2 meds

If goal BP not reachedA. Reinforce Adherence B. Add or titrate drugs above C. Add drugs from other classes

JNC 8 Algorithm

Managing Hard to Treat Hypertension

Renin-Angiotensin-Aldosterone Regulation of Blood Pressure

Blood Pressure

Vasoconstriction

Angiotensin IRenin

SubstrateAngiotensin II

Renin

Sodium & Water

Reabsorption

Aldosterone

http://vasoactivetherapy.com/files/CORLOPAM.PPT

The role of aldosterone is to retain sodium in the face of chronic deficiency

Adrenal Cortex

Adrenergic Tone

Angiotensin

Cardiac Output

Catecholamines

Adrenal Gland

CNS

Arteries

Resistance

Sympathetic Nervous System Regulation of Blood Pressure

Afterload

Blood Pressurehttp://vasoactivetherapy.com/files/CORLOPAM.PPT

Reninsecretion

Aldosterone

Adapted from : Third National Health and Nutrition. Examination Survey, Hypertension 1995;25:305-13

30-39 40-49 50-59 60-69 70-79 80

70

80

110

130

150

Age

30-39 40-49 50-59 60-69 70-79 80

70

80

110

130

150

Age

Men Women

PPPP

Blood Pressure Distribution in the Population According to Age

PP=Pulse Pressure.

7

Determinants of Blood Pressure

BP = CO x TPR

Young CO TPR

Middle Aged CO TPR

Elderly CO TPR

CLINICAL PEARL # 1

Avoid lowering the diastolic blood pressure below 55-60 mm Hg as coronary perfusion may be

compromised if DBP is too low

190

170

150

130

110

907 8 9 10 11 12 1

Time (hours)

SB

P (

mm

Hg)

ELDERLY

YOUNG

Postural Changes in Blood Pressure are more common as we Age

www.gerontologyindia.com/ppt/presentation-htn-elderly.ppt

CLINICAL PEARL # 2

Always measure BP in the standing as well as the sitting position in the very elderly as

orthostatic hypotension is common

Resistant hypertension is defined by a blood pressure ‘that is not at goal’ despite adherence to treatment with full doses of at least three antihypertensive medications, including a diuretic.

JNC 7

Resistant Hypertension Most cases of Resistant Hypertension are caused by:

Sodium excess

Extracellular volume expansion

Sympathetic overactivation

Too Much Salt

Too Much Water

Too Much Sympathetic Activity

8

Resistant hypertension is primarily a systolic and age related problem

Diastolic BP goal achieved ≥ 90% in the major trials

Systolic BP goal achieved 60-65% in the major trials

True resistance occurs in about 15%

Resistant Hypertension is more common in the elderly

CAUSES OF RESISTANT HTN

Failure to adhere to the medical regimen

White Coat Hypertension

Secondary HTN

Inappropriate or inadequate treatment

Exogenous substances

• Certain medications

• Excess body weight

• SALT

Cause of ResistanceCause of resistance found in 133/141 – 94% (83/91 – 91%) cases

Drug-relatedcauses

58%

Nonadherence16%

Unknown6%

Officeresistance

6%

Psychologicalcauses

9%

SecondaryHTN5%

Interferingsubstances

1%

Garg JP, et al. Am J Hypertens 2003;16:925-930

DBP = diastolic blood pressure; SBP = systolic blood pressure.Adapted from: Stevens VJ et al. Ann Intern Med. 2001;134:1-11; Messerli FH et al. In: Griffin BP et al, eds. 2004. Manual of Cardiovascular Medicine. 2nd ed; Whelton SP et al. Ann Intern Med. 2002;136:493-503; Cutler JA et al. Am J Clin Nutr. 1997;65(suppl):643S-651S; Xin X et al. Hypertension. 2001;38:1112-1117; Whelton PK et al. JAMA. 1997;277:1624-1632.

Nonpharmacologic Interventionsand BP Reduction

BP

Dec

reas

e(m

m H

g)

SBP DBP

ExerciseLow-Salt

DietAlcohol

ReductionPotassiumRepletion

5

4

3

2

1

0

6

7

Weight Loss(19.4 lb)




Secondary HTN





• SALT

White Coat Hypertension (WCH)

Elevated office BP in absence of true HTN Up to 40% of patients have some white coat

effect• Magnitude varies

Larger magnitude:• Taken by physician• Older patients• Higher baseline pressure

If there is true hypertension, there is often target organ damage

9

Prevalence of TOD in Refractory Hypertension

55*58*

65*

73*

22

2932

38

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

LVH Intima Media CarotidPlaques

Grade II

Refractory HTN Control Group

Thickness Retinopat

Cuspidi et al. J Hypertension 2001, 19:2063-2070

At a minimum check ECG (LVH), fundus

exam (retinopathy) and urine dipstick

(proteinuria) …and consider ABPM

CLINICAL PEARL # 3

In cases of suspected white coat hypertension, Medicare will

reimburse an ABPM under ICD-9 code 796.2 . “Elevated blood pressure reading without diagnosis of hypertension”




Secondary HTN





• SALT

Coarctation of aorta

Renal Artery StenosisRenin tumorGlomerulonephritisDM nephrosclerosisPolycystic diseaseCollagen diseaseChronic Pyelonephritis

HyperaldosteronismCushing syndromeThyroid DiseaseAcromegalyHyperparathyroidismPheochromacytoma

Drug InducedSleep ApneaPreeclampsia

Causes of Secondary HypertensionCauses of Secondary Hypertension

CONGENITAL

RENAL

ENDOCRINE

OTHER

Prevalence of Secondary Causes of Hypertension

COMMON RARESleep Apnea

(Very Common)

Pheochromocytoma (<0.5%)

Renal Disease (1-8%) Coarctation of Aorta (<1%)

Hyperaldosteronism

(1.5-15%)

Cushing’s Syndrome (0.5%)

Renal Artery Stenosis

(3-4%)

Acromegaly

Obstructive Sleep Apnea

Obstructive Apnea• Apnea/Hypopnea

• Hypoxia

• Hypercapnia

Resumption of breathing

• Labile blood pressure

EEG arousals

• Fragmented sleep

• Increased sympathetic activity

In resistant hypertension 96% of men and 65% of women have OSA

Sympathetic over activation is cause Reduction of blood pressure (BP) and heart rate (HR)

after 6 months of CPAP treatment

10

Effect of CPAP on Blood Pressure

Becker et al, 2003

Changes in blood pressure with effective (blue bars) vs subtherapeutic (orange bars) nCPAP.

15

10

5

0

-5

-10

-15

-20

-25

MAP systolic diastolic

mm

Hg

* * *

CLINICAL PEARL # 4

Obstructive Sleep Apnea is a Common Cause of Resistant

Hypertension which can be improved with effective OSA therapy

Most cases of Primary Hyperaldosteronism (PH) are caused by bilateral adrenal hyperplasia

PH often causes spontaneous hypokalemia (<3.5 mmol/L) or profound diuretic-induced hypokalemia (<3.0 mmol/L), or hypertension refractory to treatment with 3 or more drugs.

Screening for Primary Aldosteronism:

• Aldosterone >15 ng%

• Aldosterone / Renin Ratio (ARR) > 26 - 30

Hyperaldosteronism Screening for hyperaldosteronismScreening for hyperaldosteronism should include ARR

- measured in morning samples.

- sitting position after resting at least 15 minutes.

Beta-blockers• ↓ renin, but also ↓ aldosterone so no effect on ARR

Angiotensin receptor blockers >ACE-I• False NEGATIVE ARR (↓aldosterone, ↑renin)

Diuretics• ↑ both aldo and renin, so ARR doesn’t change much• Spironolactone (aldosterone antagonist) must be stopped

Calcium channel blockers• Minimal effects

Aldosterone / Renin Ratio (ARR) > 26 - 30

-21

-10

-23

-10

-25

-12

-30

-25

-20

-15

-10

-5

0

BP

res

po

nse

(m

m H

g)

6wk 3mo 6mo

Systolic BP Diastolic BP

Nishizaka MK, et al. Am J Hypertens 2003;16;925-930

Spironolactone

EXTREME Caution if K+ > 5.0 or Cr > 2.5; monitor K+

CLINICAL PEARL # 5

Hyperaldosteronism is more common than previously thought and is a cause of many cases of

resistant hypertension

11

Spironolactone treatment of patients with resistant hypertension

Chapman N et al. Hypertension. 2007;49:839-845

From the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

EXTREME Caution if K+ > 5.0 or Cr > 2.5; monitor K+

CLINICAL PEARL # 6

Aldosterone excess is seen even in the absence of Primary aldosteronism,

thus many patients with resistant hypertension benefit from a trial of an

aldosterone antagonist personal communication Franz Messerli




Secondary HTN





• SALT

Cause of ResistanceCause of resistance found in 133/141 – 94% (83/91 – 91%) cases

Drug-relatedcauses

58%

Nonadherence16%

Unknown6%

Officeresistance

6%

Psychologicalcauses

9%

SecondaryHTN5%

Interferingsubstances

1%

Garg JP, et al. Am J Hypertens 2003;16:925-930

“Rule of TENS for SBP”

1 Additional Drug for Every Additional

10 mmHg Reduction in Blood Pressure

A 10

A 10

BaselineMonotherapy

- 20

- 30

A 10

C 10

B 10

mmHg

B 10

Cushman W and Basile J. of Clinical Hypertension

Target BP (mm Hg)Number of antihypertensive agents

1Trial 2 3 4

AASK MAP <92

UKPDS DBP <85

ABCD DBP <75

MDRD MAP <92

HOT DBP <80

IDNT <135/<85

ALLHAT <140/90

DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.Lewis EJ et al. N Engl J Med. 2001;345:851-860.Cushman WC et al. J Clin Hypertens. 2002;4:393-405.

Multiple BP Lowering Agents are needed to reach Goal

12

CLINICAL PEARL # 7

Failure to use enough medication is a common cause of “resistant”

hypertension

Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014

• A prospective, multi-center, randomized, blinded, sham controlled study to evaluate both the safety and efficacy of percutaneous renal artery denervation in patients with severe treatment-resistant hypertension.

• The trial included 535 patients enrolled by 88 participating US centers.

Simplicity - 3

Results: Population DemographicsCharacteristic

mean ± SD or %

Renal Denervation

(N=364)

Sham Procedure(N=171 ) P

Age (years) 57.9 ± 10.4 56.2 ± 11.2 0.09Male sex (%) 59.1 64.3 0.26

Office systolic blood pressure (mm Hg) 180±16 180±17 0.7724 hour mean systolic ABPM (mm Hg) 159±13 160±15 0.83

BMI (kg/m2) 34.2 ± 6.5 33.9 ±6.4 0.56Race* (%) 0.57

African American 24.8 29.2White 73.0 69.6

Medical history (%) Renal insufficiency (eGFR<60) 9.3 9.9 0.88

Renal artery stenosis 1.4 2.3 0.48Obstructive sleep apnea 25.8 31.6 0.18

Stroke 8.0 11.1 0.26Type 2 diabetes 47.0 40.9 0.19

Hospitalization for hypertensive crisis 22.8 22.2 0.91


Baseline Hypertensive TherapyCharacteristic

mean ± SD or %Renal Denervation

(N=364)Sham Procedure

(N=171 )

No. of antihypertensive medications 5.1 ± 1.4 5.2 ± 1.4ACE inhibitors

% at max tolerated dose

49.2

45.9

41.5

37.4Angiotensin receptor blockers


50.0

49.5

53.2

51.5Aldosterone antagonists 22.5 28.7

Alpha-adrenergic blockers 11.0 13.5Beta blockers 85.2 86.0

Calcium channel blockers


69.8

57.1

73.1

63.7Centrally-acting sympatholytics 49.2 43.9

Diuretics


99.7

96.4

100

97.7Direct renin inhibitors 7.1 7.0

Direct-acting vasodilators 36.8 45.0


Primary Efficacy Endpoint

0

50

100

150

200

Denervation Sham

Baseline

6 Months

∆ = -14.1±23.9

P<0.001

∆ = -11.7±25.9

P<0.001

∆ = -2.39 (95% CI, -6.89 to 2.12)

P=0.26*

(N=364) (N=171)

Offi

ce S

BP

(m

m H

g)

(N=353) (N=171)

180 mm Hg

166 mm Hg

180 mm Hg

168 mm Hg

*P value for superiority with a 5 mm Hg margin; bars denote standard deviations Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014

Diuretics and BP Control

• In states of sodium (and water) excess, diuretics are essential

• Most classes of antihypertensive agents lead to sodium retention, as compensation for lower BP

• JNC 8 recommends a thiazide-type diuretic, as one of four initial antihypertensive choices in the general population

• JNC 8 recommends a thiazide-type diuretic, as one of twp initial antihypertensive choices in the Black patients

13

CLINICAL PEARL # 8

In many patients with HTN, adequate diuresis is ESSENTIAL

for BP control

Which “Thiazide”?

Thiazide

• Hydrochlorothiazide

• Chlorthiazide (Diuril®)

• Bendroflumethiazide (Naturetin®) [Bendroflumethiazide / Nadolol (Corzide®)]

Thiazide-like

• Metolazone

• Indapamide (Lozol®)

• Chlorthalidone (Thalitone® , Hygroton®)

Thiazide Diuretics Differ in Their Antihypertensive Effects

Ch

ang

e in

Am

bu

lato

ry S

ysto

lic

Blo

od

Pre

ssu

re (

mm

Hg

)W

eek

8–

Wee

k 0

Ernst ME, et al. Hypertension. 2006;47:352-358,

-30

-26

-22

-18

-14

-10

-6

-2

2

6

Hours 6am 8am 10am 12pm 2pm 4pm 6pm 8pm 10pm 12am 2am 4am

Hydrochlorothiazide 50 mg dailyChlorthalidone 25 mg daily

OfficeBlood Pressure*

–7.6 ± 2.8–17.4 ± 2.9p = 0.069

–9.3 ± 3.2–19.6 ± 3.4p = 0.109

–10.8 ± 3.5–17.1 ± 3.7p = 0.842

Week 2 Week 4 Week 6 Week 8–4.5 ± 2.1

–15.7 ± 2.2p = 0.001 CLINICAL PEARL # 9

In patients with Resistant Hypertension switching the diuretic from HCTZ to Chlorthalidone may

improve BP control

Chlorthalidone vs. HCTZ

For patients with resistant or difficult-to-control HTN, chlorthalidone appears to lower BP more effectively than hydrochlorthiazide.

If Chlorthalidone is initiated, serum K+ must be monitored after 1 and 4 weeks to avoid hypokalemia. Serum Na+ must be monitored periodically to avoid hyponatremia.




Secondary HTN





• SALT

14

Medications that can exacerbate HTN Salt, H2O retention)

• NSAIDs, COX-2 inhibitors (Celecoxib) • Hormone therapy, Oral Contraceptive Pills (OCPs)• Steroids• Cyclosporine• Excessive black licorice ingestion (aldoseterone-like)

Sympathetic Overactivity• Sympathomimetic agents (decongestants)• Diet pills, Cocaine, Ephedrine • Stimulants (Methylphenidate, Amphetamine)• herbal compounds (ephedra)• SSRIs (parasympathetic withdrawal = sympathetic

overactivity)• Alcohol (binge drinking, >30 ml/day) ?• Erythropoietin ?

Effect of Ibuprofen (400 mg qid) for 3 weeks on supine BP in 30 treated hypertensive patients

-6

-4

-2

0

2

4

6

8

Placebo Ibuprofen

Diff

eren

ce (

mm

Hg)

Diastolic BP Systolic BP

Radak et al, 1987




Secondary HTN





• SALT

NHANES III Prevalence of Hypertension According to BMI

14.9 15.2

22.1

27.727

32.7

41.937.8

0

10

20

30

40

50

Men Women

BMI <25 BMI 25-<27 BMI 27-<30 BMI > 30

*Defined as mean systolic blood pressure 140 mm Hg, mean diastolic 90 mm Hg, or currently taking antihypertensive medication.

Brown C et al. Body Mass Index and the Prevalence of Hypertension and Dyslipidemia. Obes Res. 2000;8:605-619.

Per

cen

t w

ith

HT

N




Secondary HTN





• SALT (Sodium excess + potassium defecit)

Sodium (Salt)

15

Effects of Reduced Na+ on BP and CVD Events: Results from 3 Randomized Trials

TRIAL OUTCOME FU

TONE 639 elderly pts - weight loss and sodium restriction, following withdrawal of BP medications

21%↓CV events

2.3 y

Taiwan Veterans 1,981 elderly Taiwanese, living at a Veteran’s home; table salt substituted with a potassium salt

41%↓ CV Mortality

2.6 y

TOHP Follow-up 3,126 pts with Prehypertension (30-54 y.o,)dietary sodium reduction

30%↓ CV events

10-15 y

1Appel, Arch Int Med, 2001; 2Chang, AJCN, 2006; 3Cook, BMJ, 2007

Salt Sensitivity can be decreased with increased potassium intake

J Am Coll Nutr June 2006 vol. 25 no. suppl 3 262S-270S

Salt sensitivity was measured in AA and white men.

Following this they were maintained on diets of varying K+ levels.

On a low K+ diet, 80% of AA and 35% of white men were salt sensitive

As potassium intake was increased, salt sensitivity decreased.

On a high K+ diet, only 20% of the AA men, and no white men were still salt sensitive

How low potassium leads to HTN:• Low Potassium triggers cells to gain sodium in

order to maintain their tonicity and volume • Sodium depolarizes cellular membranes, leading

to vasoconstriction (HTN)• As sodium enters body, water follows, this

causes extracellular volume expansion (HTN).

How Potassium reduces blood pressure• Potassium hyperpolarizes cellular membranes,

thereby relaxing blood vessels. • Potassium increases salt excretion (as above).

Water follows, thus there is a diuretic effect.

Hypokalemia. In: Adrogue HJ, Wesson. DE. Potassium. Boston: Blackwell Scientific, 1994:89-164.

The Role of Potassium in Hypertension The Role of Potassium in Hypertension Potassium deficit is critical in hypertension

Recent evidence as well as classic studies point to the interaction of sodium and potassium, as compared with an isolated abnormality of either alone, as a dominant factor in hypertension

Processed foods are high in sodium and low in potassium; Conversely, fruits and vegetables are sodium-poor and potassium-rich

This is the basis for the DASH diet which is rich in potassium rich fruit and vegetables

-Whelton PK. Potassium and blood pressure. In: Izzo JL Jr, Black HR, eds. Hypertension primer. 3rd ed. Dallas: American Heart Association/Council on High Blood Pressure Research, 2003:280-2.-He FJ, MacGregor GA. Beneficial effects of potassium. BMJ 2001;323:497-501

CLINICAL PEARL # 10

In patients with Hypertension it is very difficult to control BP unless the serum K+ can be maintined

above 4.0 mmol/l. DASH diet is a great way to increase K+ levels




Secondary HTN





• SALT (Sodium excess + potassium defecit)

16

Hypertension 2014

Hypertension is common and will likely affect most individuals at some point in their lifetime

Guidelines on how best to treat hypertension are evolving and sometimes contradictory

For information on prevention, detection and evaluation of hypertension, JNC 7 and international guidelines offer guidance

OSA and hyperaldosteronism are the most common secondary causes of resistant HTN

Inadequate treatment is also a common cause of resistant HTN (rule of 10s)

Potassium sufficiency is critical to BP control

Questions?

jnc 8 & conquering hard-to-treat hypertension files/spring 2014 syllabu… · 1 session 6...

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