HYPERTENSION When, what, co-morbid conditions ? George Mangos DEPARTMENT OF MEDICINE ST GEORGE HOSPITAL UNSW

HYPERTENSIONWhen, what, co-morbid

conditions ?

George Mangos

DEPARTMENT OF MEDICINEST GEORGE HOSPITAL

www.med.unsw.edu.au/stgrenal

UNSW

When to start treatment?

• 40 yo male, confirmed Blood Pressure • 144/92 mmHg (St 1)?• 160/84 mmHg (St 2)?• 136/84 mmHg (high(n))?

• 61 prospective observational studies of BP (Oxford University)• N > 1 000 000 !• 12.7 million person-years• 56000 vascular deaths• Cardiovascular outcomes using original raw data

Prospective Studies Collaboration Lancet 2002

120 140 160 180

1

2

4

8

16

32

64

128

256

Usual systolic blood pressure (mmHg)

Str

oke

mor

talit

y(f

loat

ing

abso

lute

ris

ks &

95%

CI)

Age at risk: 20 mmHg SBP

80-89 33% risk

70-79 50% risk

60-69 57% risk

50-59 62% risk

(40-49 64% risk)

11 274 deaths at ages 50 - 89

Stroke mortality rate in each decade of age versus usual SBP at the start of that decade

Age at risk: 10 mmHg DBP

80-89 37% risk

70-79 52% risk

60-69 60% risk

50-59 66% risk

(40-49 65% risk)


Stroke mortality rate in each decade of age versus usual DBP at the start of that decade

Usual diastolic blood pressure (mmHg)70 80 90 100 110

1

2

4

8

16

32

64

128

256

Str

oke

mor

talit

y(f

loat

ing

abso

lute

ris

ks &

95%

CI)

IHD mortality rate in each decade of age versus usual SBP at the start of that decade

Age at risk 20 mmHg SBP

80-89 31% risk

70-79 40% risk

60-69 46% risk

50-59 50% risk

40-49 51% risk


Usual systolic blood pressure (mmHg)120 140 160 180

1

2

4

8

16

32

64

128

256

IHD

mor

talit

y(f

loat

ing

abso

lute

ris

ks &

95%

CI)

Age at risk 10 mmHg DBP

80-89 30% risk

70-79 38% risk

60-69 44% risk

50-59 48% risk

40-49 53% risk

IHD mortality rate in each decade of age versus usual DBP at the start of that decade


Usual diastolic blood pressure (mmHg)70 80 90 100 110

1

2

4

8

16

32

64

128

256

IHD

mor

talit

y(f

loat

ing

abso

lute

ris

ks &

95%

CI)

Prospective Studies Collaboration

tells us that the risk of hypertension;• Continues through normal BP range• Risk is stronger than originally thought• Reduction in BP 10 / 5 mmHg

• 40% reduced risk of stroke death• 30 % reduced risk of IHD or other

vascular death• Benefit of lower BP extends to 115/75

mmHg

“incremental increases of 20/10 systolic/diastolic blood pressure beginning with values of 115/75 result in a doubling of cardiovascular risk mortality.”

PSC Meta-analysis – Summary

Evidence that rising BP and risk is

overwhelming• Predictive• Reproducible• Independent• Continuous• All populations

When to Start Therapy ?

High Normal Blood Pressure 136/84 mmHg

• “Prehypertension” – benefit from treatment with candesartan for 2 years in healthy young males

• Lower rates of subsequent hypertension

N Engl J Med 2006; 355:1551-1562, Oct 12, 2006;

Slide SourceHypertensionOnline

www.hypertensiononline.org

HOPE StudyHOPE Study

• The Heart Outcomes Prevention Evaluation (HOPE) Study was a multicenter, randomized trial enrolling 9,297 patients 55 years old with a history of cardiovascular disease, or diabetes plus at least one other cardiovascular risk factor

• Patients were treated with ramipril or placebo and vitamin E or placebo for an average of 4.5 years

• Combined primary endpoint was the development of myocardial infarction, stroke, or cardiovascular death

• Secondary endpoints were total mortality, admission to hospital for congestive heart failure or unstable angina, complications related to diabetes, and cardiovascular revascularization

Yusuf S, et al. N Engl J Med. 2000;342:145-153.



HOPE Study Outcomes: HOPE Study Outcomes: Events Per Patient GroupEvents Per Patient Group

0

5

10

15

20

Placebo Ramipril

Combined Primary

Outcome*

Cardio-vascular

Death

Myocardial Infarction

Stroke Non-Cardiovascular

Death

Total Mortality

Yusuf S, et al. N Engl J Med. 2000;342:145-153.

RR=22%P<0.001

RR=26%P<0.001

RR=20%P<0.001

RR=32%P<0.001

RR=16%P=0.005

RR=0%P=NS

RR=Relative risk reduction

Even

ts p

er

pati

en

t g

rou

p (

%)

*The occurrence of myocardial infarction, stroke or cardiovascular death



When to Start Therapy ?When to Start Therapy ?

HOPE Study

• In presence of TOD it is probably beneficial to start ACEI in high risk patients, regardless of blood pressure.

High – Normal BP(130-139/85-89 mmHg)

• No TOD• Lifestyle modifications

• TOD• Consider ACEI or ARB

Lifestyle modifications to manage hypertension

Modification Recommendation SBP Reduction

Weight loss BMI 18.5-24.9 5-20 mmHg/10kg

DASH plan 8-14 mmHg

Na reduction < 100 mmol or 6g salt 2-8 mmHg

Physical Activity 30 min/day, most days

4-9 mmHg

Moderation EtOH Max 2/day men, 1/day women

2-4 mmHg

JNC VII Report 2003. JAMA 289 2560-2572

Stage 1 hypertension (140-159/90-99 mmHg)

• Lifestyle Modification for 6 months BUT• Microalbuminuria• Hypertensive retinopathy• eGFR < 60• PVD• LVH or IHD• Cerebrovascular disease

Treatment SHOULD be initiatedTarget Organ Damage

Stage 2 hypertension

• 160/84 mmHg• Once confirmed, treatment SHOULD be

initiated• Lifestyle modification recommended• Isolated Systolic Hypertension

0

1

2

3

4

Rela

tive r

isk o

f C

HD

mort

ality

He J, et at. Am Heart J. 1999;138:211-219.

<112

<71

CHD Death according to SBP and DBP in MRFIT (n=350,000)

1 2 3 4 5 6 7 8 9 10Decile

112-

71-

118-

76-

121-

79-

125-

81-

129-

84-

132-

86-

137-

89-

142-

92-

>151

>98

SBP

DBP

Systolic blood pressure

Diastolic blood pressure

0123456789

Rela

tive r

isk o

f str

oke d

eath

<112

<71

Stroke Death According to SBP and DBP in MRFIT (n=350,000)

1 2 3 4 5 6 7 8 9 10

112-

71-

118-

76-

121-

79-

125-

81-

129-

84-

132-

86-

137-

89-

142-

92-

>151

>98

SBP

DBP

Systolic blood pressure

Diastolic blood pressure

He J, et at. Am Heart J. 1999;138:211-219.

0

20

40

60

80

100

Ag

e-a

dju

ste

d a

nn

ual C

VD

even

t ra

te p

er

10

00

Wilking SV et al. JAMA. 1988;260:3451-3455.

Men Women

Isolated Systolic Hypertension and Cardiovascular Disease Risk in Framingham

ISH BP 160/<95 mmHg

BP <140/95 mmHg82

4333

2.4

18

2.5

P<0.001 for difference between both men and women with ISH and blood pressure (BP) <140/95 mmHg

CLINICAL PEARL

• Systolic hypertension is a more important risk factor than diastolic blood pressure.

How low to treat ?

Is there a J-Curve ?

0 mmHg Blood Pressure 200 mmHg

CV Disease

risk

Is there a J-Curve ?

0 mmHg Blood Pressure 200 mmHg

CV Disease

risk

Evidence for J-curve

BP = 0 mmHg –> patient is dead

“Overwhelming evidence now that our BP targets should be much lower.”

TREATING TO TARGET

How low should our BP targets be ?

Do we achieve BP targets in treatment of hypertension ?

HOT

Slim Jim /NK/1 14/05/20041

HypertensionOptimalTreatmentInternational Study

HypertensionOptimalTreatmentInternational Study

HOTHOT Study resultsStudy results

0

80

85

90

95

100

105

0 3 6 12 24 36 Finalfollow-up

74%

43%

DBPmm Hg

target 80 mm Hg

86%73%55%

target 85 mm Hg

target 90 mm Hg

HOT - Target blood pressure is an achievable goal

(% patients reaching target)

60%60%

Hansson et al 1998

Months

Risk of a major cardiovascular event reduced by 30% in the HOT Study

0

5

10

15

20

25

30

105 100 95 90 85

% risk reduction

Optimal DBPreduction in theHOT Study

Hansson et al 1998

Achieved DBPmm Hg80

Significant benefits from intensive blood pressure reduction in

diabetics

0

5

10

15

20

25

90 85 80 mm HgTarget DBP

Major CV events/1000 patient years

Hansson et al 1998

p=0.005 for trend

HOT -HOT - Combination therapy needed to achieve target blood pressure

Monotherapy

Combinationtherapy

59%59% 32%32%

SBP/DBPmm Hg 161/98 142/83

SBP/DBPmm Hg 140/81

26%26%

80 mm Hg

142/83

32%32%

85 mm Hg

144/85

37%37%

90 mm Hg

Enrolment Final

Hansson et al 1998

HOT Study results (1998)

No difference in achieved BP between the 3 groups (85.2 mmHg, 83.2 mmHg, and 81.1 mmHg)

No difference in CV outcomes between groups BEST OUTCOMES AT 139/83 mmHg No J-curve demonstrated 70 % of patients required 2 or more drugs BP targets achieved in > 50-80 % subjects

HOT Study Group. Lancet. 1998;351(9118):1755-1762.

Heart Foundation Guidelines 2004

Targets• Adults > 65 < 140/90 mmHg• All others <130/85 mmHg• Proteinuria > 1g < 125/75 mmHg

“MOST of your patients will require combined therapy”

Randomized Design of ALLHAT BP Trial

42,41842,418

High-risk High-risk hypertensive hypertensive patientspatients

Consent / Consent / RandomizeRandomize

AmlodipineAmlodipine

ChlorthalidoneChlorthalidone

DoxazosinDoxazosin

LisinoprilLisinopril

Follow until death or end of study (4-8 years, mean 4.9 years)Follow until death or end of study (4-8 years, mean 4.9 years)

ALLHATALLHAT

Inclusion Criteria

Men and women aged > 55 years

Seated blood pressure (2 categories):

1) Treated for @ least 2 months.

2) Not on drugs or on drugs < 2

months.

Additional risk factor or target organ damage.

ALLHATALLHAT

Blood Pressure Control

31

58 60 64 67 67

92%91%90%88%86%

68% 6665625855

27

0

20

40

60

80

100

0 1 2 3 4 5

Years of Follow-up

Per

cen

t

DBP<90 SBP<140 BP<140/90

ALLHATALLHAT

Cushman, et al. J Clinical Hypertens 2002; 4:393-404

CLINICAL PEARL #2

• It is often more difficult to control systolic blood pressure than diastolic blood pressure.

0

20

40

60

80

100

0

0.4

0.8

1.2

1.6

2

ALLHAT Treatment and Blood Pressure Control

6 mos 1 yr 3 yr 5 yr

1 Drug 2 Drugs 3 Drugs

Pati

en

ts (

%)

Cushman WC, et al. J Clin Hypertens. 2002;4:393-405.

Avera

ge #

of d

rug

s

Blood pressure controlled <140/90 mmHg

49.8% 55.2% 62.3% 65.6%

1.41.4

1.71.7

2.02.0

1.31.3

Proportion of Uncontrolled ALLHAT Participants Not

Stepped Up at Annual Visits

59

68 69 72 72

0

20

40

60

80

1 2 3 4 5

Years

Pe

rcen

t

Cushman, et al. J Clinical Hypertens 2002; 4:393-404Cushman, et al. J Clinical Hypertens 2002; 4:393-404

Average Number of AntiAverage Number of Anti--Hypertensive Hypertensive Agents Used to Achieve Target BPAgents Used to Achieve Target BP

2.7

~75

<75 mmHgDBP

ABCD

2.83.33.6Avg # of drugs per

patient

828193Achieved

BP

<85 mmHgDBP

<80 mmHgDBP

<92 mmHgMAP*

Goal BP

UKPDSHOTMDRD

* The goal mean arterial pressure (MAP) of <92 mmHg specified in the MDRD trial corresponds to a systolic/ diastolic blood pressure of approximately 125/ 75 mmHg.


CLINICAL PEARLS #3-5

• Monotherapy only effective in only 30-40% patients

• Treating down to targets IS possible in most patients

• Doctors do not always follow guidelines, even in studies.

16 %*6 %*

18 %

20 %

34 %

9 %

19 %

2.5 %

Hypertension – Target BP !(<160/95, *<140/90)

JNC VI. Arch Int Med 1997;157:2413Colhourn et al. J Hypertens 1998;16:747Marques-Vidal et al. J Hum Hypertens 1997;11:213

Heart Foundation Guidelines 2004

Targets• Adults > 65 < 140/90 mmHg• All others <130/85 mmHg• Proteinuria > 1g < 125/75 mmHg

“MOST of your patients will require combined therapy”

How do we get blood pressure under control ?

• Non-pharmacological Measures

• Pharmacotherapy




DASH plan 8-14 mmHg



4-9 mmHg


2-4 mmHg


Dietary Approaches to Stop Hypertension (DASH) Study

• Published 1997 NEJM• N=459• DBP 80-95 mmHg• SBP < 160 mmHg• 8 weeks

DASH Study - design

control diet

v

‘fruit/vegetable rich diet’

v

‘combination diet’

Results – (n=133)

• BP was controlled in 70 % of Stage 1 hypertensives (140-159/90-95) with combination diet

• No weight loss, no change Na+ or Ca++ intake• Increased K and Mg intake in combination diet

group• ? Long term sustainability• ? CV endpoints

DASH – Results (n=133)




DASH plan 8-14 mmHg



4-9 mmHg


2-4 mmHg


Which Drugs to Use?Which Drugs to Use?

70

75

80

85

90

130

135

140

145

150

ALLHAT Mean Systolic and Diastolic ALLHAT Mean Systolic and Diastolic Blood Pressure During Follow-upBlood Pressure During Follow-up

Systo

lic B

P (

mm

Hg

)

Follow-up, yrs0 1 2 3 4 5 6 0 1 2 3 4 5 6

Dia

sto

lic B

P (

mm

Hg

)

Chlorthalidone

Amlodipine

Lisinopril

Chlorthalidone

Amlodipine

Lisinopril

ALLHAT Research Group. JAMA. 2002;288:2981-2997.

Compared to chlorthalidone:

DBP significantly lower in amlodipine group (~1

mmHg).

Compared to chlorthalidone:

SBP significantly higher in amlodipine (~1 mmHg) and

lisinopril (~2 mmHg) groups.

0

4

8

12

16

20

ALLHAT Primary Outcome – Cumulative ALLHAT Primary Outcome – Cumulative fatal CHD and non-fatal MIfatal CHD and non-fatal MI

Cu

mu

lati

ve F

ata

l C

HD

an

d

Non

fata

l M

I even

t ra

te (

%)

Time to event (yrs)

0 1 2 3 4 5 6 7

Chlorthalidone

Amlodipine

Lisinopril


0

2

4

6

8

10

ALLHAT Stroke by Treatment ALLHAT Stroke by Treatment GroupGroup

0 1 2 3 4 5 6 7

Cu

mu

lati

ve e

ven

t ra

te (

%)

Chlorthalidone

Amlodipine

Lisinopril

Time to event, yrs


0

3

6

9

12

15

ALLHAT Heart Failure ALLHAT Heart Failure by Treatment Groupby Treatment Group

0 1 2 3 4 5 6 7

Cu

mu

lati

ve e

ven

t ra

te (

%)

Chlorthalidone

Amlodipine

Lisinopril

Time to event, yrs

P<0.001 for chlorthalidone vs amlodipine and chlorthalidone vs lisinopril


Special Groups

• JNC VII

23

Overall ConclusionsALLHAT

Because of the superiority of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first-step antihypertensive drug therapy.

ANPB2 – ACEI v thiazide

• 65-84 yrs both sexes• > 160 systolic OR > 90 diastolic mmHg• Few previous cardiovascular events• 6000 patients followed for average 4.1 years• ACEI or HCTZ 1st line

• CCB, - or -blocker added to achieve target.• Target: > 20 sys. and > 10 dias. fall to

< 160/90 (140/80 mmHg if tolerated)• Family practices

Wing L et al 2003 NEJM

ANBP2 - BP after Randomisation

ANBP2 – Results

• 5 yrs - BP decreased by 26/12 mm Hg both groups

• monotherapy - 65 % ACEI gp- 67 % diuretic gp

Target not tight.• 60 % of subjects continued with initial

treatment

ANBP2 – Primary endpoints

• Cardiac - ACEI > diuretics• Stroke - diuretics > ACEI• Death - similar both agents

“ACE-inhibitor-based therapy resulted in an outcome advantage over a diuretic-based regimen, despite similar reductions in blood pressure ..”

ANBP2 – Conclusions

• N=162,341• Overview of 29 RCTs • Effects of Different Blood Pressure

Lowering Regimens on Major Cardiovascular Events

• Trials including ACEI, CCBs, ARBs, b-blockers, diuretics

Blood Pressure Lowering Treatment Triallists Collaboration

BPLTTC Lancet 2002. 362:1537-35

BPLTTC Trials• Active v placebo

• HOPE, PART2, PROGRESS, QUIET, SCAT• CCB v placebo

• IDNT, NICOLE, PREVENT, SYST-EUR• More v Less

• AASK, ABCD, HOT, UKPDS• ARB v control

• IDNT, RENAAL, SCOPE, LIFE• Different Drug Classes

• ACEI - AASK, ALLHAT, ANBP2, CAPPP, STOP2• CCB – AASK, CONVINCE, ELSA, INSIGHT, NICS,

NORDIL, SHELL, STOP-2• ACE v CCB – AASK, ABCD, ALLHAT, JMIC-B, STOP-2

RESULTS

ACEI and CCB v placebo • More Rx better

than less for stroke and CV events

• CCBs show no benefit for CCF

BPLTTC Lancet 2003

ARBs v Placebo• Benefits of ARBs observed in stroke, CCF and

major CV events. • ARBs probably now treatment of choice in type 2

DM with microalbuminuria (IRMA) or overt proteinuria (RENAAL/IDNT)

STUDIES COMPARING DRUG CLASSES

Stroke• Borderline significance ? ACEI

inferior to D/BB and CCBCHD• No difference between ACEI,

D/BB and CCBCHF• ACEI and D/BB superior to

CCBMajor CV Events• No differencesCV Death• No differencesTotal Mortality• No differences

Dual Blockade of the RAS with ARBs and ACEI

• CALM Study (2000) – candesartan + lisinopril well tolerated and lower BP

• Jacobsen et al (2003) – irbesartan + enalapril lower BP and proteinuria in T1DM

• Rossing et al (2002) – candesartan + ACEI lower BP and proteinuria

• Hard endpoints lacking

How to achieve target BP

• CONTRACT with the patient in the first or second visit• Education, literature• Understanding of

rationale of treatment• Multiple drug therapy

LIKELY• Patient involved in

decision making• Lifestyle factors

• The outcome is NOT being on treatment rather identifying the problem (HT) and the target BP and using means the get there.

Valsartan Antihypertensive Long-Term Use

Evaluation

2004

VALUE Study

VALUE: SignificanceVALUE: Significance

• First trial to compare a modern angiotensin II receptor blocker (ARB), valsartan, to the most widely used third-generation calcium channel blocker, amlodipine

• Designed to evaluate effectiveness of a valsartan-based regimen vs an amlodipine-based regimen on overall cardiac outcomes

• N=15,000

Mann J, Julius S. Blood Press. 1998;7:176–183.

Effects of Angiotensin II at ATEffects of Angiotensin II at AT11 and AT and AT22 ReceptorsReceptors

Blocked by ARBs

ATAT2AT1

- Vasoconstriction- Aldosterone release- Oxidative stress- Vasopressin release- SNS activation- Inhibits renin release - Renal Na+ and H2O reabsorption- Cell growth and proliferation

- Vasodilation- Antiproliferation- Apoptosis- Natriuresis- Bradykinin production- NO release

Siragy H. Am J Cardiol. 1999;84:3S–8S.

VALUE: Systolic Blood Pressure in Study

Julius S et al. Lancet. June 2004;363.

Valsartan (N= 7649)

Amlodipine (N = 7596)

135

140

145

150

155

mm

Hg

Months (or final visit)

Sitting SBP by Time and Treatment Group

Baseline 1 24 482 3 4 6 12 18 30 36 42 54 60 66

01.02.03.04.0

1 24 48

mm

Hg

2 3 4 6 12 18 30 36 42 54 60 66Months (or final visit)

5.0Difference in SBP Between Valsartan and Amlodipine

–1.0

VALUE: Diastolic Blood Pressure in Study


Valsartan (N= 7649)

Amlodipine (N = 7596)

mm

Hg

Months (or final visit)

Sitting DBP by Time and Treatment Group

mm

Hg

Baseline 1 24 482 3 4 6 12 18 30 36 42 54 60 66

75

85

80

90

0

1.02.0

1 24 482 3 4 6 12 18 30 36 42 54 60 66

Months(or final visit)

3.0

Difference in DBP Between Valsartan and Amlodipine

–1.0

4.0

5.0

VALUE: Primary Composite Cardiac Endpoint

14

12

10

8

6

4

2

0

Time (months)

0 6 12 18 24 30 36 42 48 54 60 66

Pro

port

ion

of

Pati

en

ts W

ith

Fir

st

Even

t (%

)Valsartan-based regimen

Amlodipine-based regimen

HR = 1.03; 95% CI = 0.94–1.14; P = 0.49


Number at risk

Valsartan

Amlodipine 7596

7649

7469

7459

7424

7407

7267

7250

7117

7085

6772

6732

6955

6906

6576

6536

5959

5911

3725

3765

1474

1474

6391

6349

VALUE: Fatal and Non-fatal Stroke


Number at risk

Valsartan

Amlodipine 7596

7649

7499

7494

7455

7448

7334

7312

7195

7170

6918

6877

7055

7022

6744

6692

6163

6093

3846

3859

1532

1516

6587

6515

6

5

4

3

2

1

0

Time (months)0 6 12 18 24 30 36 42 48 54 60 66

Pro

port

ion

of

Pati

en

ts

Wit

h F

irst

Even

t (%

)Valsartan-based regimen


HR = 1.15; 95% CI = 0.98–1.35; P = 0.08

Time (months)Number at risk

Valsartan

Amlodipine 7596

7649

7497

7499

7458

7458

7332

7319

7205

7177

6905

6853

7065

7016

6727

6680

6141

6078

3840

3864

1532

1520

6562

6504

Pro

port

ion

of

Pati

en

ts W

ith

Fir

st

Even

t (%

)

7

6

5

4

3

2

1

0

VALUE: Fatal and Non-FatalMyocardial Infarction

0 6 12 18 24 30 36 42 48 54 60 66

Valsartan-based regimen


HR = 1.19; 95% CI = 1.02-1.38; P = 0.02


Number at risk

Valsartan

Amlodipine 7596

7649

7486

7485

7444

7444

7312

7312

7176

7169

6874

6852

7033

7012

6702

6671

6100

6072

3823

3860

1511

1513

6534

6498

VALUE: Heart Failure

Time (months)0 6 12 18 24 30 36 42 48 54 60 66

9

8

7

6

5

4

3

2

1

0

Valsartan-based regimen


HR = 0.89; 95% CI = 0.77-1.03; P = 0.12

Pro

port

ion

of

Pati

en

ts

Wit

h F

irst

Even

t (%

)


Hospitalisation for HF or death from HF

VALUE: Incidence of New-onset DiabetesVALUE: Incidence of New-onset DiabetesN

ew

-On

set

Dia

bete

s

(% o

f p

ati

en

ts in

t

reatm

en

t g

rou

p)


0

2

4

6

8

10

12

14

Valsartan-based Regimen

(n = 5254)

Amlodipine-based Regimen

(n = 5168)

13.1%

16.4%

23% Risk Reduction With Valsartan

16

18

P < 0.0001

VALUE: Other Results

• Incidence of stroke was lower, but not significantly, in the amlodipine group

• Incidence of non-fatal MI was significantly lower in the amlodipine group

• There was a positive trend in favour of valsartan for less heart failure but this did not reach significance

• There was a highly significant lower rate of new-onset diabetes in the valsartan group


ONTARGET Study• ONgoing Telmisartan Alone and in

Combination with Ramipril Global Endpoint Trial• to determine if the combination of the ARB

telmisartan and the ACE inhibitor ramipril is more effective than ramipril alone

• If telmisartan is at least as effective as ramipril. • n=25,000, HOPE-like patients• Recruitment completed July 2003• Follow up 3.5-5 yrs

TRANSCEND Study

• The Telmisartan Randomized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease (TRANSCEND)• determine if telmisartan is superior to placebo in

patients who are intolerant of ACE inhibitors. • HOPE like patients• N=5700 (/6000)• Follow up 3.5-5 yrs

Causes of Secondary Hypertension

• Renal Artery Stenosis• Phaeochromocytoma• Primary Aldosteronism• Alcohol Excess• Obesity**• Cushing’s Disease• Low Aldo / Low Renin syndromes

• Sensitivity – ability of a test to detect a true positive

• Specificity – ability of a test to detect true negative

New screening tests for hypertension

• Positive Predictive Value – probability that a positive test is a true positive (ie detects true disease)

• Negative Predictive Value – probability that a negative test is a true negative (ie excludes disease

New screening tests for hypertension

Renal Artery Stenosis

• Atherosclerotic RAS• Fibromuscular Hyperplasia• Takayasu’s Arteritis

• 19% of patients with CAD have RAS • Rates of progression of RAS low

• 31% over 3 years• Intervention studies have failed to reliably show

benefit of angioplasty+stenting of a-s RAS

Zierler 2003 Mayo Proceedings

Doppler US diagnosis of RAS

• Papers generally by radiologists• Sensitivity 95% (60-80%)• Specificity 90%

• Problems described• Training operators • Operator dependent• Study takes 1 hour• Body habitus influences technical success• Accessory renal arteries not visualized

• 20-27% population

Rabbia 2003

• Attractive• Cheap (and subsidised)• Non-invasive• ‘add-on’ when imaging the kidneys• Anyone can order test

Doppler US diagnosis of RAS

Contrast enhanced sonography in the diagnosis of renal artery stenosis

Argalie et al Radiologica Medica 2004

• 51 patients with suspected RAS• 11 excluded because “renal artery not well

visualised”• DSA showed RAS in 16/40 pts (40%)• Sensitivity 75% (colour doppler)

100% (power doppler)• Specificity 79% and 88%

• Correcting for excluded patients

• Sensitivity 50% (colour doppler)80% (power doppler)

Contrast enhanced sonography in the diagnosis of renal artery stenosis

Argalie et al Radiologica Medica 2004

Captopril Renal Scan

• Sensitivity 84-100%• Specificity 62-100%

• Strengths• Functional Test• Relatively Non-Invasive

• Weaknesses• Less sensitive if CRF present• Can’t be taking an ARB or ACEI

CT Angiography

• Sensitivity > 90 %• Specificity > 90 %

• Problems• Contrast (often > 100 mls)• Accessory arteries not well seen• Ca++ affects stenosis interpretation• Compared favourably to US (Halpern 1998)

• Sensitivity 96 v 63%

MR Angiography

• Sensitivity 97% (c/w 69% US)• Specificity > 95% (Qanadli 2001)

• Problems• Availability & cost• Metallic implants• Co-operation, breath-holding and

claustraphobia

RAS Summary

• DSA remains gold standard for diagnosis• Screening for atherosclerotic disease has

problems;• Non-invasive tests unreliable• Percutaneous interventions unproven• Morbidity of angioplasty significant

• US/CT/captopril tests may be useful in patients with high pre-test probability

Phaeochromocytoma tests

• 24 hr urinary VMA• 24 hr urinary catecholamines• Plasma catecholamines• 24 hr total urinary metanephrines

(spectrophotometry)

Recently (liquid chromatography)• 24hr urinary fractionated metanephrines• Plasma free metanephrines (continuous leak from

tumour cells)

Catecholamine metabolism

Test Comparisons

Test Sensitivity Specificity

Plasma Metanephrines 97 % 85 %

24hr U total metanephrines + catecholamines

90 % 98 %

Sawka et al, JCEM, 2003

Test Comparisons(hypertensives prevalence = 0.5%)

Test Positive Predictive Value

Negative Predictive Value

Plasma Metanephrines 3 % 99.98 %

24hr U total metanephrines + catecholamines

23 % 99.95 %

Sawka et al, JCEM, 2003

Testing for Phaeochromocytoma

Plasma Metanephrines ?

Met <0.4Normet <0.7

Met 0.4-1.2Normet 0.7-2.2

Met > 1.2Normet > 2.2

Very low likelihood of phaeochromocytoma

Small tumour possible (familial)

False positive (sporadic)

High likelihood of phaeochromocytoma

•Drugs (β & α blockers, symnpathomimetics, TCA•Repeat after overnight fast +•Measure 24hr urine metanephrines and catecholamines

Metanephrine Summary

• Tumours usually show levels > x3-4 normal• Specificity about 85%, 15% false positives (usually < x3-4

normal)• Increase with age (? Age corrections)• If low positive, repeat after overnight fast and avoid drugs• Urine metanephrines have very high specificity (good to

exclude false positive)• Less variability in response to external factors• Urine catecholamines provide little extra information

“Rule of 10’s”

• Phaeochromocytoma• 10% extraadrenal

• 10% extraabdominal• 10% malignant• 10% bilateral• 10% hereditary

Dluhy RG, 2002, NEJM

Familial Phaeochromocytoma

• 24% of patients with sporadic phaeochromocytoma had a germ-line mutation of one of 4 phaeo-predisposing genes;• VHL gene• RET proto-oncogene• SDHD• SDHB

Neumann et al 2002 NEJM.

Autosomal Dominant Phaeochromocytoma-predisposing Syndromes

Syndrome Phenotype Risk of Phaeo.

Mutated Germ-Line Gene

MEN 2A MTC, HPTH 50 % RET

MEN 2B MTC, marfanoid, mucosal neuromas, HPTH

50 % RET

Neurofibromato-sis type 1

Neurofibromas, café au lait spots

1 % NF1

VHL disease Retinal angioma, CNS haemangioblastomas, renal cysts & Ca

10-20 % VHL

Familial Paraganglioma Syndrome

Carotid body tumours (chemodectoma)

20 % SDHD, SDHB

Dluhy RG, 2002, NEJM

THANK YOU

Dr Peter Campbell & team

Daya Naidoo (SEALS)

www.med.unsw.edu.au/stgrenal

Primary Aldosteronism

• Dr J Conn – suppressed plasma renin in normo- and hypokalaemic subjects

• ? Rare• Traditionally 0.4 % incidence• Several groups described PAL in 5-15

% of HT patients (Gordon 1994)• Aldosterone/renin ratio as initial

screening test• Our centre 3 % of HT cohort

Aldosterone:renin ratio

• Aldosterone : renin ratio• Normal range ?• Interfered with by drugs

• False positive: b blockers• False negative: ACEI, Ca antagonists,

diuretics• Suspension of medication difficult

Establish Dx of PAL

• Positive A/R ratio may not be PAL• Suppression test required to demonstrate

autonomy of aldosterone production• Saline loading (2L/4 hrs)

• False negatives• Fludrocortisone suppression (0.4 mg/day 5

days)• Admission, hypoK

• Always consider Familial Hyperaldosteronism - 1

FH-1

Localizing tests

• ? Unilateral or bilateral production• Cannulation of adrenal veins• Aldosterone and cortisol

• (R) adrenal vein difficult

Aldosterone Cortisol

Left 12860 1107

Right 600 162

Peripheral 458 159

PAL

• 1/3 of patients with PAL will have unilateral production (lateralize) of aldosterone• ½ of these will be cured by surgery• ½ will require less medication• Some will recur in contralateral gland

• 2/3 of patients with PAL have bilateral production of aldosterone - medication

Documents

HYPERTENSION When, what, co-morbid conditions ? George Mangos DEPARTMENT OF MEDICINE ST GEORGE HOSPITAL UNSW