6/3/2015

1

Thinking Beyond New Clinical Guidelines:

Update in Hypertension

John Standridge, MD, FAAFP, FASAM

Clinical Professor

Departments of Family Medicine and Internal Medicine

UTCOM Chattanooga

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).

Hypertension is the most common condition seen in primary care and leads

to myocardial infarction, stroke, renal failure, and death if not detected early

and treated appropriately. Patients want to be assured that blood pressure

(BP) treatment will reduce their disease burden, while clinicians want

guidance on hypertension management using the best scientific evidence.

This report takes a rigorous, evidence-based approach to recommend

treatment thresholds, goals, and medications in the management of

hypertension in adults. Evidence was drawn from randomized controlled

trials, which represent the gold standard for determining efficacy and

effectiveness. Evidence quality and recommendations were graded based

on their effect on important outcomes. There is strong evidence to support

treating hypertensive persons aged 60 years or older to a BP goal of less

than 150/90 mm Hg and hypertensive persons 30 through 59 years of age

to a diastolic goal of less than 90 mm Hg; however, there is insufficient

evidence in hypertensive persons younger than 60 years for a systolic goal,

or in those younger than 30 years for a diastolic goal, so the panel

recommends a BP of less than 140/90 mm Hg for those groups based on

expert opinion.

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).

The same thresholds and goals are recommended for hypertensive adults

with diabetes or nondiabetic chronic kidney disease (CKD) as for the

general hypertensive population younger than 60 years. There is

moderate evidence to support initiating drug treatment with an

angiotensin-converting enzyme inhibitor, angiotensin receptor blocker,

calcium channel blocker, or thiazide-type diuretic in the nonblack

hypertensive population, including those with diabetes. In the black

hypertensive population, including those with diabetes, a calcium channel

blocker or thiazide-type diuretic is recommended as initial therapy. There

is moderate evidence to support initial or add-on antihypertensive therapy

with an angiotensin-converting enzyme inhibitor or angiotensin receptor

blocker in persons with CKD to improve kidney outcomes. Although this

guideline provides evidence-based recommendations for the management

of high BP and should meet the clinical needs of most patients, 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.

Thinking Beyond New Clinical Guidelines:

Update in Hypertension

Hypertension is one of the most common conditions managed by

generalists and is a major risk factor for multiple conditions. Surrounded

by great debate, the committee appointed to the Eighth Joint National

Committee published their suggestions for new hypertension treatment

guidelines in early 2014. We suggest a new target blood pressure (BP) for

the general population older than 60 years of less than 150/90 mm Hg, up

from less than 140/90 mm Hg as recommended by the Seventh Joint

National Committee, and in diabetic patients, a goal of less than 140/90

mm Hg, up from the Seventh Joint National Committee recommendation

of less than 130/80 mm Hg. Regardless of the BP target

recommendations suggested by the Eighth Joint National Committee and

other organizations, obtaining accurate BP readings and recognizing

white-coat and masked hypertension is imperative. Home and ambulatory

BP monitoring are useful tools in addition to proper in-office BP readings.

The optimal care of the hypertensive patient involves accurate BP

characterization, careful use of guidelines, and good clinical judgment.

Benjamin R. Griffin, MD, Carrie A. Schinstock, MD. Mayo Clin Proc. 2015 Feb;90(2):273-9.

Commentary on the 2014 BP guidelines from the panel

appointed to the Eighth Joint National Committee (JNC 8).

The recently published article "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)" (James et al., JAMA 311: 507-520, 2014)

has generated considerable controversy. In this commentary, we evaluate the

document and compare the recommendations contained within it with those of the

JNC 7 and other national and international guidelines. The evidence quality rating

approach followed by the article "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)" (James et al., JAMA

311: 507-520, 2014) disqualified nearly 98% of previous studies from review;

as a result, some of the key recommendations were on the basis of expert

opinion alone. We are especially concerned that the recommendation to raise

the systolic/diastolic BP levels at which treatment is initiated to ≥150/≥90

mmHg in adults≥60 years old may affect cardiovascular and renal health in

these patients. Additionally, we recommend that hypertension guidelines should be

updated every 3-4 years with a fresh approach to the definition of target BP levels,

the use of modern technology in the diagnosis of hypertension, and the treatment of

hypertension in special populations not addressed in earlier guidelines.

J Am Soc Nephrol. 2014 Nov;25(11):2419-24

The Hypertension Syndrome

Obesity/ adiposity

Abnormal lipid metabolism

Accelerated atherogenesis

Left ventricular hypertrophy

and dysfunction

Changes in blood clotting mechanisms

Changes in renal function

Endothelial dysfunction

Abnormal glucose

metabolism

Abnormal insulin

metabolism

Abnormalities of neuro- hormonal function

Decreased arterial

compliance

Hypertension

Syndrome

6/3/2015

2

WHY Treat Hypertension?

• Hypertension is the most common chronic

condition treated by family physicians.

• Elevated blood pressure is associated with

an increased risk of heart failure,

myocardial infarction, cerebrovascular

disease, renovascular disease, and death.

• Treatment of hypertension reduces the

risk of these events.

MRFIT: Elevation of SBP Exerts Greater Effects on Coronary Artery Disease

Mortality

Implications of Hypertension

• The public health

goal of treating

hypertension is the

reduction of the

atherothrombotic

cardiovascular

sequelae of heart

disease, stroke,

renovascular

disease, and death

Renin Angiotensin System, Ang II,

and End-Organ Damage1-6

Glomerular capillary pressure Proteinuria Aldosterone release Glomerular sclerosis

Atherosclerosis Vasoconstriction Vascular inflammation and hypertrophy Endothelial dysfunction

Left ventricular hypertrophy Fibrosis Remodeling Apoptosis

Stroke

Death

Hypertension

Heart Failure Myocardial Infarction

Renal Failure

Brain

Vessels

Heart

Kidney

Angiotensin II

Age-specific relevance of usual blood pressure to vascular

mortality: a meta-analysis of individual data for

one million adults in 61 prospective studies.

• Meta-analysis of 61 prospective, observational studies

• 1 million adults

• 12.7 million person-years

• FINDINGS: Within each decade of age at death, the proportional difference in the risk of vascular death associated with a given absolute difference in usual blood pressure is about the same down to at least 115 mm Hg usual systolic blood pressure (SBP) and 75 mm Hg usual diastolic blood pressure (DBP), below which there is little evidence. At ages 40-69 years, each difference of 20 mm Hg usual SBP (or, approximately equivalently, 10 mm Hg usual DBP) is associated with more than a twofold difference in the stroke death rate, and with twofold differences in the death rates from IHD and from other vascular causes. All of these proportional differences in vascular mortality are about half as extreme at ages 80-89 years as at ages 40-49 years, but the annual absolute differences in risk are greater in old age. The age-specific associations are similar for men and women, and for cerebral haemorrhage and cerebral ischaemia. For predicting vascular mortality from a single blood pressure measurement, the average of SBP and DBP is slightly more informative than either alone, and pulse pressure is much less informative.

• INTERPRETATION: Throughout middle and old age, usual blood pressure is strongly and directly related to vascular (and overall) mortality, without any evidence of a threshold down to at least 115/75 mm Hg.

Lewington S, et.al., Lancet 2002;360:1903-1913.

BP Reduction Is Critical; the Lower, the Better

Data show that lowering blood pressure

by 10 mm Hg in patients with hypertension

reduces cardiovascular and stroke mortality

by 25% and 40%, respectively. Ogihara T, Saruta T, Matsuoka H, et al. Hypertens Res. 2004;27(9):657–661.

6/3/2015

3

Benefits of BP Reduction in the Hypertension

Optimal Treatment (HOT) Trial: Diabetic Cohort

•Achieved = mean of all BPs from 6

months of follow-up to end of study

•81.1 •139.7 • 80

•83.2 •141.4 • 85

•85.2 •143.7 • 90

•Achieved

DBP

(mm Hg)

•Achieved

SBP

(mm Hg)

•Target

DBP

(mm Hg)

P = 0.05 for trend

Adapted from Hansson L, et al. Lancet. 1998;351:1755-62.

Ma

jor

CV

Eve

nts

(p

er

10

00

pa

tie

nt

yrs

)

Achieved DBP (mm Hg)

0

25

50

85.2 83.2 81.1

Relationship Between SBP

Reduction and CV Mortality

Staessen JA, et al. Lancet. 2001;358:1305-15. Difference in SBP (mm Hg)

Od

ds r

ati

o

P = 0.003

0 5 10 15 20 25 - 5

HOPE

MIDAS/NICS/VHAS

UKPDS C vs A

NORDIL INSIGHT

HOT L vs H HOT M vs H STOP ACEIs

STOP CCBs

CAPPP UKPDS L vs H

Syst-China

STONE

Syst-Eur

MRC1 MRC2

SHEP HEP

EWPHE

RCT70-80

STOP-1

PART 2/SCAT ATMH

1.50

1.25

1.00

0.75

0.50

0.25

―High-Normal‖ BP Is Not Benign ―High-Normal‖ BP Is Not Benign

Difference in Number of CV Events

When BP is Controlled

Adapted from JNC7 – Evidence from clinical trials

-60

-50

-40

-30

-20

-10

0

Stroke

Myocardialinfarction

Heart failure

-35 to 40% Stroke rate

-20 to 25% Rate of MI

>50% Reduction in CHF

Cardiovascular Mortality Risk Doubles With Each 20/10 mm Hg BP Increment*

6/3/2015

4

Midlife Hypertension and 20-Year Cognitive Change The Atherosclerosis Risk in Communities Neurocognitive Study

• Importance Hypertension is a treatable potential cause of cognitive decline

and dementia, but its greatest influence on cognition may occur in middle age.

• Main Outcomes and Measures Prespecified outcomes included the 20-year

change in scores on the Delayed Word Recall Test, Digit Symbol Substitution

Test, and Word Fluency Test and in global cognition.

• Results Having a JNC-8–specified indication for initiating antihypertensive

treatment at baseline was associated with a greater 20-year decline (−0.044

[95% CI, −0.085 to −0.003] global z score points) than not having an indication.

Each 20–mm Hg increment at baseline was associated with an additional

decline of 0.048 (95% CI, −0.074 to −0.022) points in global cognitive z score

in whites but not in African Americans. Individuals with hypertension who used

antihypertensives had less decline during the 20 years than untreated

individuals.

• Conclusions and Relevance Midlife hypertension and elevated midlife but

not late-life systolic BP was associated with more cognitive decline during the

20 years of the study. Greater decline is found with higher midlife BP in whites

than in African Americans

JAMA Neurol. 2014;71(10):1218-1227.

WHEN To Treat

Cochrane review vs Ann Intern Med

• A Cochrane review concluded that treatment of patients

with mild hypertension (SBP of 140 to 159 mm Hg and

DBP of 90 to 99 mm Hg) did not reduce morbidity or

mortality compared with placebo.1

• However, a more recent (2015) meta-analysis that

included data from additional trials found that treatment

of mild hypertension reduced strokes, cardiovascular

deaths, and total deaths after five years.2

• No good-quality RCTs have assessed the benefits of

treating elevated DBP in persons younger than 30 years.

1. Diao D, et al. Pharmacotherapy for mild hypertension.

Cochrane Database Syst Rev. 2012;(8):CD006742.

2. Sundstrom J, et al. Effects of blood pressure reduction in mild hypertension

Ann Intern Med. http://annals.org/article.aspx?articleid=2085847. Accessed January 6, 2015.

Effects of Blood Pressure Reduction in Mild

Hypertension: A Systematic Review and Meta-analysis

• Study Selection: Patients without cardiovascular disease with blood

pressures in the grade 1 hypertension range (140 to 159/90 to 99 mm

Hg) who were randomly assigned to an active (antihypertensive drug

or more intensive regimen) or control (placebo or less intensive

regimen) blood pressure–lowering regimen.

• Data Synthesis: The average blood pressure reduction was about

3.6/2.4 mm Hg. Over 5 years, odds ratios were 0.86 (95% CI, 0.74 to

1.01) for total cardiovascular events, 0.72 (CI, 0.55 to 0.94) for strokes,

0.91 (CI, 0.74 to 1.12) for coronary events, 0.80 (CI, 0.57 to 1.12) for

heart failure, 0.75 (CI, 0.57 to 0.98) for cardiovascular deaths, and 0.78

(CI, 0.67 to 0.92) for total deaths. Results were similar in secondary

analyses. Withdrawal from treatment due to adverse effects was more

common in the active groups.

• Conclusion: Blood pressure–lowering therapy is likely to prevent

stroke and death in patients with uncomplicated grade 1 hypertension.

Ann Intern Med. 2015;162(3):184-191

WHEN To Treat

JNC 8 • The JNC 8 panel concluded that there is strong evidence

of benefit for treating DBP greater than 90 mm Hg in

adults older than 30 years and for treating SBP greater

than 150 mm Hg in adults older than 60 years.

• Based on expert opinion, they recommend that SBP

greater than 140 mm Hg be treated in adults younger

than 60 years.

• The panel also recommends that if an adult undergoing

treatment has a blood pressure below these goals and

there are no adverse effects from treatment, the

antihypertensive regimen should not be changed.

James PA, et al. 2014 evidence-based guideline for the management of high blood pressure in adults

[published correction appears in JAMA. 2014;311(17):1809]. JAMA. 2014;311(5):507–520.

JNC 8: Relaxing the Standards

• Evidence-based guidelines are indispensable and assist clinicians in

providing the most effective care for patients. The Eighth Joint

National Committee (JNC 8) recently issued the most anticipated

guideline in some time.

• The JNC 8 committee was initially appointed in 2008 by the National

Heart, Lung, and Blood Institute. When the National Institutes of

Health discontinued sponsorship of clinical recommendations, JNC

8 panel members published their guideline on the management of

hypertension in the Journal of the American Medical Association the

same week the American Society of Hypertension and the

International Society of Hypertension released their guideline.

• The JNC 8 guideline was never endorsed by the American Heart

Association or the American College of Cardiology.

Editorial by ROBERT GAUER, MD, and JUSTIN LAROCQUE, PharmD, BCPS,

Published in Am Fam Physician. 2014 Oct 1;90(7):449-452.

JNC 8: Relaxing the Standards

• More than 25% of older adults who were receiving

antihypertensive therapy under the more stringent JNC 7

targets will be reclassified as at goal under JNC 8, suggesting

that millions of Americans are eligible for reduction or

elimination of antihypertensive therapy.

• However, the panel recommended that therapy not be

adjusted for these patients, which creates two distinct

standards within the same age group.

• Do we know which group is receiving better care?

• Are we fostering a healthier population or merely tolerating

higher blood pressure values?

Editorial by ROBERT GAUER, MD, and JUSTIN LAROCQUE, PharmD, BCPS,

Published in Am Fam Physician. 2014 Oct 1;90(7):449-452.

6/3/2015

5

JNC 8: Relaxing the Standards

• As in JNC 7, physicians have been challenged to stay within

the performance measures of blood pressure goals. With

more relaxed blood pressure targets for older adults, it is

conceivable that clinicians may become less vigilant and be

satisfied with near-goal values. Will these slightly higher blood

pressure targets improve care for patients or result in higher

rates of cardiovascular and cerebrovascular events?

• Patients who met the JNC 7 requirements for hypertension

should be maintained on their current regimen. For others,

achieving a systolic blood pressure closer to 140 mm Hg,

compared with 150 mm Hg, is reasonable given the available

evidence, assuming that the adverse effects of medication are

minimal.

Editorial by ROBERT GAUER, MD, and JUSTIN LAROCQUE, PharmD, BCPS,

Published in Am Fam Physician. 2014 Oct 1;90(7):449-452.

Evolution of SBP Classification

Evolution of DBP Classification Current Hypertension Guidelines

• Journal of the American Medical Association (JAMA)

• American Diabetes Association (ADA)

• Hypertension Canada

• European Society of Hypertension (ESH)

• The International Society of Hypertension (ISH) and World

Health Organization

• The International Society on Hypertension in Blacks

(ISHIB)

• Journal of Clinical Hypertension (JCH)

• National Heart, Lung, and Blood Institute (NHLBI)

• National Institute for Health and Clinical Excellence (NICE)

• National Kidney Foundation (NKF)

Why Treat

When to Treat

HOW to Treat

Patient Evaluation –

Focused History with 3 Objectives

• Assess lifestyle and identify other CV risk

factors or concomitant disorders that may

affect prognosis or guide treatment

• Reveal identifiable causes of high BP

• Assess the presence or absence of

target-organ damage (TOD) and CVD

6/3/2015

6

Identifiable Causes of Hypertension

• Sleep apnea

• Drug-induced or drug-

related

• Chronic kidney

disease

• Primary

aldosteronism

• Renovascular disease

• Chronic steroid

therapy and Cushing

syndrome

• Pheochromocytoma

• Coarctation of the

aorta

• Thyroid or parathyroid

disease

Physical Examination

• Appropriate measurement of BP

– Verification in the contralateral arm

• Optic fundoscopy

• BMI calculation

• Auscultation for carotid,

abdominal, and femoral bruits

• Palpation of the thyroid gland

• Thorough exam of the heart

and lungs

• Abdominal exam for enlarged kidneys, masses, bruits, and abnormal aortic pulsation

• Lower extremities for edema and pulses

• Neurologic assessment

Initial Laboratory Evaluation of Hypertension

12-lead electrocardiography

Blood glucose level

Fasting cholesterol panel (including low-density lipoprotein and high-

density lipoprotein cholesterol, triglycerides)

Glomerular filtration rate

Hematocrit level

Serum calcium level

Serum potassium level

• Optional

– Urinary albumin excretion

– Albumin/creatinine ratio

Components of the Dietary Approaches

to Stop Hypertension (DASH) Diet

Dietary component

Amount

Total fat 27% of calories

Saturated fat 6% of calories

Cholesterol 150 mg

Carbohydrates 55% of calories

Fiber 30 g

Protein 18% of calories

Sodium 1,500 mg

Lifestyle Recommendations

for Lowering Blood Pressure Consume a diet that emphasizes intake of vegetables, fruits, and whole grains;

includes low-fat dairy products, poultry, fish, legumes, nontropical vegetable

oils, and nuts; and limits intake of sweets, sugar-sweetened beverages, and red

meat. Adapt this dietary pattern to appropriate caloric requirements, personal

and cultural food preferences, and nutritional therapy for other medical

conditions (including diabetes mellitus). Follow plans such as the DASH diet,

the U.S. Department of Agriculture Food Patterns, or the American Heart Association diet.

Consume no more than 2,400 mg of sodium per day. Further reduction of

sodium intake to 1,500 mg per day is associated with even greater reduction in

blood pressure. Reducing intake by at least 1,000 mg per day will lower blood

pressure even if the desired daily intake is not achieved.

Combine the DASH diet with lower sodium intake.

In general, advise adults to engage in aerobic physical activity to lower blood

pressure (three or four 40-minute sessions of moderate to vigorous activity per

week).

Lifestyle Modifications for Hypertension

• Lose weight if overweight (80% of type 2 diabetics)

• Limit EtOH to 1 oz. (2 beers/wine/drinks) for men,

0.5 oz for women and lighter weight men

• Increase aerobics to 30-45 min. most days

• Reduce Na+ to 2.4 g; Reduce saturated fat

• Adequate potassium, Ca++, and Mg++

• Stop smoking; Control lipids

6/3/2015

7

Anatomy of Health Effects of Mediterranean diet:

Greek EPIC prospective cohort study

• High

• Vegetables

• Fruits

• Nuts

• Beans

• Olive oil

• Wine /alcohol (in moderation)

• Minimal

• Fish

• Whole grains

• Low fat dairy

• Low

– Meats

Trichopoulou A, et al. BMJ 2009;338;b2337

Mediterranean diet

• Two studies in coronary patients, the Lyon Diet

Heart Study and the IndoMediterranean Diet

study, have shown that, despite no difference in

fasting lipid levels, a Mediterranean diet reduced

myocardial infarction and death by 60% in four

years and by 50% in two years compared with

diets amounting to the American Heart

Association diet that is usually prescribed to

coronary patients.

Spence JD. Fasting lipids: The carrot in the snowman.

Can J Cardiol. 2003 Jul;19(8):890-2.

Evolution of Antihypertensive Therapy

1950s 2015

Diuretics

Vasodilators

Sympatholytics

B-Blockers ACEIs ARBs

Volume CCBs

Vasoconstriction

Renin-Angiotensin System

FDR was

tx’ed with

phenobarbitol

Roosevelt died two months after the Yalta Conference of a brain hemorrhage.

DRIs

Examples of Clinical Trials That Have Impacted Hypertension Treatment

Management

Evolution of Treatment Recommendations

JNC 8 recommendations represent a

paradigm shift in the pharmacologic

management of hypertension • Thiazide diuretics had previously been recommended as

monotherapy for patients with stage 1 hypertension or in

combination with other agents for patients with stage 2

hypertension.

• Now, thiazides, angiotensin-converting enzyme inhibitors,

angiotensin receptor blockers, and calcium channel blockers

are indicated for monotherapy.

• There is insufficient evidence that beta blockers provide

clinically significant benefits for cardiovascular and

cerebrovascular outcomes.

• The availability of four first-line agents may seem more

challenging, but it allows clinicians to incorporate their

preferences—and those of their patients—into the accepted

practice recommendations.

6/3/2015

8

Initial Antihypertensive Drug

Selection by Patient Population

Patient population

American Society of

Hypertension guideline1

European Society of

Hypertension/European

Society of Cardiology

guideline2

Black patients CCB or thiazide diuretic CCB or thiazide diuretic

Nonblack patients

younger than 60 years

ARB or ACE inhibitor CCB, thiazide diuretic,

ARB, ACE inhibitor, or

beta blocker

Nonblack patients 60

years and older

CCB, thiazide diuretic,

ARB, or ACE inhibitor

CCB or thiazide diuretic

Patients with chronic

kidney disease

ARB or ACE inhibitor ARB or ACE inhibitor

1. Weber MA, et al. Clinical practice guidelines for the management of hypertension

in the community. J Clin Hypertens (Greenwich). 2014;16(1):14–26.

2. Mancia G, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension.

Eur Heart J. 2013;34(28):2159–2219.

JNC-7 Compelling Indications:

Clinical Trials and Guideline Basis High-Risk Conditions

With Compelling Indications

Recommended Drugs Aldosterone Diuretic BB ACEI ARB CCB Antagonist

Clinical Trial Basis

Heart Failure + + + + + Post- MI + + + + High coronary + + + + + disease risk Diabetes + + + + + Chronic kidney disease + + Recurrent stroke + + prevention

ACC/AHA HF guidelines, RALES, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT

ACC/AHA Post-MI guidelines, BHAT, SAVE, Capricorn, EPHESUS

ALLHAT, HOPE, ANBP2, LIFE, CONVINCE, VALIANT (NEJM 2003;349:1893-906)

NKF-ADA Guideline, UKPDS, ALLHAT

NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK

PROGRESS

Efficacy and Safety of Benazepril for

Advanced Chronic Renal Insufficiency

NEJM Volume 354:131-140

January 12, 2006

• Benefits did not appear to be attributable to blood-pressure control.

• Benazepril therapy was associated with a 52 percent reduction in the level of proteinuria and a reduction of 23 percent in the rate of decline in renal function.

• Group 1 had a serum creatinine level of 1.5 to 3.0 mg per deciliter, and group 2 had a serum creatinine level of 3.1 to 5.0 mg per deciliter at baseline.

Kaplan–Meier Estimates of the Percentage of Patients Not Reaching

the Primary Composite End Point of a Doubling of the Serum

Creatinine Level, End-Stage Renal Disease, or Death

• As compared with placebo, benazepril was associated with a 43 percent reduction in the risk of the primary end point in group 2 (P=0.005).

• Benazepril conferred substantial renal benefits in patients without diabetes who had advanced renal insufficiency

Multiple Antihypertensive Agents

Are Needed to Achieve Target BP

Concomitant Use of

Antihypertensive Drugs

Less effective

Diuretics -Blockers

ACEIs ARBs and

aliskiren

Calcium

Channel

Blockers 1-Receptor Blockers

Particularly effective

Adapted from Chalmers J. Clin Exp Hypertens. 1993;15:1299-1313.

6/3/2015

9

Causes of Resistant Hypertension

• Improper BP measurement

• Volume overload and pseudotoleance – Excess sodium intake

– Volume retention from kidney disease

– Inadequate diuretic therapy

• Associated conditions – Obesity

– Excess alcohol intake

• Identifiable causes of hypertension

• Drug-induced/other causes – Nonadherence

– Inadequate doses

– Inappropriate combinations

– NSAIDs/ Cox-2s

– Cocaine, amphetamines…

– Sympathometics

– Oral contraceptives

– Adrenal steroids

– Cyclosporine/tacrolimus

– Erythropoetin

– Licorice (including some chewing tobacco)

– Ephedra, ma huang, bitter orange

Commonly Used Agents:

Adverse Effects

Muscle cramps

Impotence

Gout

Dyslipidemia

Glucose

intolerance

Hypokalemia

Hyperuricemia

Hypomagnesemia

Depression

Sleep disorders

Exercise

tolerance

Dyslipidemia

Glucose

intolerance

Impotence

Edema

Flushing

Headache

Dizziness

GI disorders

Changes in

heart rate

Cough

Angioedema

Hyperkalemia

Diuretics -Blockers CCBs ACEIs ARBs

Placebo-like

Less frequent

hyperkalemia

Tolerability and Treatment Compliance

0

10

20

30

40

50

60

70

% of patients continuing prescribed drug

regimen after 1 year

ARBs

ACEIs

CCAs

BBs

Ds

Mancia G, et al. AJH Dec 2003; 16, 1066-73

White coat hypertension

not confirmed but still

likely?

Work with patient to

identify preferred and

feasible solution.

Evaluation of Resistant Hypertension

Difficult to control

blood pressure

Inaccurate measurement or

clues for whitecoat hypertension

Any antagonising substances, such as

NSAIDS or amphetamines?

Any aggravating conditions, such as

obesity or sleep

apnea?

Any problems with adherence?

Inappropriate medication regimen?

No

Yes

Yes

Yes No

No No

No

Confirmed with home

or ambulatory blood

pressure

monitoring?

Any common cause of

secondary hypertension, such

as renal vascular or renal

parenchymal disease?

Consider referral for

further evaluation

Adapted from O’Rorke JE, Richardson

WS. BMJ. 2001;322:1229-1232.

Controlled blood

pressure?

ALDOSTERONE CAUSES… • Na+/K+/H+ exchange in distal nephron

– Hypokalemia, salt/water retention, met.alk.

• ↑ catecholamine release

• ↓ NE uptake by myocardium

• ↑ oxidative stress

• ↓ fibrinolysis

• Endothelial dysfunction

• Vascular stiffening and injury

• Necrosis/fibrosis of myocardium

• Glomerulosclerosis /proteinuria

• Cardiac arrhythmias

• Heart failure

6/3/2015

10

THINK ALDOSTERONE EFFECT

WHEN….

• Serum K+ <3.5 mmol/L – Na+ >135 mmol/L

– No thiazide or loop diuretic

– Salt and water retention / edema

• BP uncontrolled w/ 3 drugs [not MRB]

• Resistant HT + sleep apnea

• Plasma aldosterone >15 ng/dl

• Plasma aldosterone/renin activity ratio >25

• Salt-loading does not suppress aldosterone

• Adrenal enlargement / mass [incidental]

Potential Advantages

of Low Dose

Combination Therapy

• Effectively reduces BP

• Maintains BP control over 24 hours with once-a-day dosing

• Effective in all hypertensive patients

• Reduced adverse events

• Reduced negative metabolic side effects

• End organ protection beyond BP control

• Cheaper than multiple drug therapy

Ideal

Antihypertensive

Agent • Effectively reduces BP

• Effective over 24 hours with once-a-day dosing

• High response rate

• Reduced adverse events

• Reduced negative metabolic side effects

• End organ protection beyond BP control

• Affordable

The kidney is a vital organ

• I call it the neglected target organ…

Renin Angiotensin System, Ang II,

and End-Organ Damage1-6

Glomerular capillary pressure Proteinuria Aldosterone release Glomerular sclerosis

Atherosclerosis Vasoconstriction Vascular inflammation and hypertrophy Endothelial dysfunction

Left ventricular hypertrophy Fibrosis Remodeling Apoptosis

Stroke

Death

Hypertension

Heart Failure Myocardial Infarction

Renal Failure

Brain

Vessels

Heart

Kidney

Angiotensin II

Glomerular Effects of CCBs vs

ACEIs and ARBs

Valentino VA et al. Arch Intern Med. 1991;151:2367-2372.

Vivian EM et al. Ann Pharmacother. 2001;35:452-463.

Dilation of afferent arteriole only Dilation of both afferent

and efferent arteriole

Glomerular pressure

Albumin excretion rate

Glomerular pressure

Albumin excretion rate

Efferent arteriole

Glomerulus

CCB TTD ACE inhibitor

ARB

Bowman’s

capsule

Afferent

arteriole

Efferent arteriole constricted by AII

Afferent

arteriole

Glomerulus Bowman’s

capsule

Aldosterone

Na+ reabsorption K+ excretion

Kidneys

Cytokine Activation Vascular Inflammation

Endothelial Dysfunction

Blood Vessels

Vascular Injury

Cardiac Hypertrophy Myocardial fibrosis

LV Hypertrophy

Heart

Blood Pressure

Hypertension

Brain

End-stage renal disease MI, HF, Sudden Cardiac Death

Emerging Science Indicates that Aldosterone Plays a Multi-Factorial Cardiovascular role

DW Kitzman

6/3/2015

11

27

Years to CHD Event0 1 2 3 4 5 6 7

Cu

mu

lative

CH

D E

ve

nt R

ate

0

.04

.08

.12

.16

.2

Number at Risk:

Chlorthalidone 15,255 14,477 13,820 13,102 11,362 6,340 2,956 209

Amlodipine 9,048 8,576 8,218 7,843 6,824 3,870 1,878 215

Lisinopril 9,054 8,535 8,123 7,711 6,662 3,832 1,770 195

Cumulative Event Rates for the Primary

Outcome (Fatal CHD or Nonfatal MI) by

ALLHAT Treatment Group

0.810.99 (0.91-1.08)L/C

0.650.98 (0.90-1.07)A/C

p valueRR (95% CI)

ALLHAT

Chlorthalidone

Amlodipine

Lisinopril

37

Overall ConclusionsALLHAT

Because of the superiority of thiazide-type

diuretics in preventing one or more majorforms of CVD and their lower cost, they

should be the drugs of choice for first-stepantihypertensive drug therapy.

A family physician questions the conclusions

from ALLHAT. Standridge JB. Am J Hypertens. 2004 Apr;17(4):361-5.

A key ALLHAT conclusion is that thiazide diuretics should be preferred for first-step antihypertensive therapy.

• ALLHAT was not a monotherapy trial, and rational drug combinations were discouraged by study design in the lisinopril limb.

• ALLHAT was not a valid comparison trial because blood pressures were not equally controlled with the various study limbs

• The ALLHAT conclusion that recommends chlorthalidone for initial hypertension therapy seems unjustified because ALLHAT was not a trial that initiated therapy for hypertension.

• ALLHAT was not of sufficient length to detect the poorer outcomes that are inevitable with increased rates of diabetes in the chlorthalidone limb.

• The heart failure subset analysis was not prospectively established.

ALLHAT was not designed to make the conclusions claimed by its authors.

Hypertension and Atherosclerosis:

Clinical Implications from the ALLHAT Trial.

Standridge JB.

• By failing to recognize the heterogeneity of hypertension, the authors of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study used a faulty premise to conduct a poorly designed clinical trial. By failing to control blood pressures equally across study drug groups, ALLHAT cannot be considered to be a definitive comparative trial. Being neither a monotherapy trial nor a trial that initiated therapy for blood pressure control, ALLHAT provided no data to recommend first-line therapy for hypertension, making the conclusions invalid.

• Thiazide-type diuretics increase angiotensin II and consequently promote atherosclerosis and arteriolarsclerosis.

• Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers retard atherosclerosis and are nephroprotective.

• Multiple randomized controlled trials show beneficial clinical outcomes, including cardioprotection and nephroprotection, with the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. These agents, and not thiazide-type diuretics, should be used as first-line agents to retard the process of atherosclerosis and its clinical outcomes in the setting of arterial hypertension.

Curr Atheroscler Rep. 2005 Mar;7(2):132-9.

A Systematic Review of Randomized Controlled

Trials Examining the Nephroprotective

Properties of Antihypertensive Medications

John B. Standridge, M.D.

Clinical Professor

Departments of Family Medicine and Internal Medicine

University of Tennessee College of Medicine

Chattanooga

Leslie Griffin, M.D.

Instructor

Department of Family Medicine

University of Tennessee College of Medicine

Chattanooga

A Systematic Review of Randomized Controlled Trials

Examining the Nephroprotective Properties of

Antihypertensive Medications

• Abstract: Introduction: Despite improved control rates of

hypertension in the United States during the last thirty

years, the rate of chronic kidney disease and end-stage

renal disease has not demonstrated a similar resultant

improvement.

• Purpose: The purpose for this review is to determine

interventions in the treatment of hypertension that

improve outcomes in the promotion of nephroprotection.

• Method: A systematic comprehensive search of the

National Library of Medicine utilizing Medline was

conducted with search limits confined to randomized

controlled trials.

Current Hypertension Reviews, Volume 8, Number 3, August 2012, pp. 196-226(31)

6/3/2015

12

A Systematic Review of Randomized Controlled Trials

Examining the Nephroprotective Properties of

Antihypertensive Medications

• Results: Angiotensin receptor blockers (ARBs) and

angiotensin-converting enzyme inhibitors (ACEIs) are

nephroprotective alone and in combination with other

classes of antihypertensive agents, but can result in

renal dysfunction when used in combination with each

other or with a direct renin inhibitor (DRI). Older L-type

calcium channel blockers (CCBs) can be nephrotoxic

when used as monotherapy. CCBs are additionally

nephroprotective when combined with ACEIs or ARBs.

Thiazide-type diuretics (TTDs) with the exception of

indapamide are not nephroprotective and TTDs may

have nephrotoxic properties.

Current Hypertension Reviews, Volume 8, Number 3, August 2012, pp. 196-226(31)

A Systematic Review of Randomized Controlled Trials

Examining the Nephroprotective Properties of

Antihypertensive Medications

• Conclusion: ACEIs and ARBs are preferred first-line

agents because they are effective in the prevention of

renal as well as cardiovascular and cerebrovascular

target organ damage associated with hypertension.

CCBs are preferred when a second medication is

needed for hypertension control. When diuretic therapy

is indicated for hypertension control, indapamide is

preferred over other TTDs for nephroprotection.

Current Hypertension Reviews, Volume 8, Number 3, August 2012, pp. 196-226(31)

Effect of angiotensin-converting enzyme inhibitors and

angiotensin II receptor blockers on all-cause mortality,

cardiovascular deaths, and cardiovascular events in

patients with diabetes mellitus: a meta-analysis.

• RESULTS: Twenty-three trials compared ACEIs with placebo or active drugs

(32,827 patients) and 13 compared ARBs with no therapy (controls) (23,867

patients). When compared with controls, ACEIs significantly reduced the risk of

all-cause mortality by 13%, CV deaths by 17%, and major CV events by 14%,

including myocardial infarction by 21% and heart failure by 19%. Treatment with

ARBs did not significantly affect all-cause mortality, CV death rate, and major

CV events with the exception of heart failure. Both ACEIs and ARBs were not

associated with a decrease in the risk for stroke in patients with DM. Meta-

regression analysis showed that the ACEI treatment effect on all-cause mortality

and CV death did not vary significantly with the starting baseline blood pressure

and proteinuria of the trial participants and the type of ACEI and DM.

• CONCLUSIONS AND RELEVANCE: Angiotensin-converting enzyme inhibitors

reduced all-cause mortality, CV mortality, and major CV events in patients with

DM, whereas ARBs had no benefits on these outcomes. Thus, ACEIs should be

considered as first-line therapy to limit excess mortality and morbidity in this

population.

JAMA Intern Med. 2014 May;174(5):773-85.