HYPERTENSION When, what, co-morbid conditions ?

1
HYPERTENSIONWhen, what, co-morbid conditions ?

• George Mangos
• DEPARTMENT OF MEDICINEST GEORGE HOSPITAL
• www.med.unsw.edu.au/stgrenal
• UNSW

2
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))?

3

• 61 prospective observational studies of BP
  (Oxford University)
• N gt 1 000 000 !
• 12.7 million person-years
• 56000 vascular deaths
• Cardiovascular outcomes using original raw data
• Prospective Studies
  Collaboration Lancet 2002

4
Stroke mortality rate in each decade of age
versus usual SBP at the start of that decade
11 274 deaths at ages 50 - 89
5
Stroke mortality rate in each decade of age
versus usual DBP at the start of that decade
11 274 deaths at ages 50 - 89
Usual diastolic blood pressure (mmHg)
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IHD mortality rate in each decade of age versus
usual SBP at the start of that decade
33 867 deaths at ages 40 - 89
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IHD mortality rate in each decade of age versus
usual DBP at the start of that decade
33 867 deaths at ages 40 - 89
8
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

9
PSC Meta-analysis Summary

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

10
Evidence that rising BP and risk is overwhelming

• Predictive
• Reproducible
• Independent
• Continuous
• All populations

11
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 3551551-1562, Oct 12, 2006

12
HOPE 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. 2000342145-153.
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HOPE Study Outcomes Events Per Patient Group
RR22 Plt0.001
RR20 Plt0.001
RR16 P0.005
RR26 Plt0.001
Events per patient group ()
RR32 Plt0.001
RR0 PNS
Combined Primary Outcome
Cardio- vascular Death
Myocardial Infarction
Stroke
Non-Cardiovascular Death
Total Mortality
The occurrence of myocardial infarction, stroke
or cardiovascular death
RRRelative risk reduction
Yusuf S, et al. N Engl J Med. 2000342145-153.
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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.

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High Normal BP(130-139/85-89 mmHg)

• No TOD
• Lifestyle modifications
• TOD
• Consider ACEI or ARB

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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 lt 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
17
Stage 1 hypertension (140-159/90-99 mmHg)

• Lifestyle Modification for 6 months BUT
• Microalbuminuria
• Hypertensive retinopathy
• eGFR lt 60
• PVD
• LVH or IHD
• Cerebrovascular disease
• Treatment SHOULD be initiated
• Target Organ Damage

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Stage 2 hypertension

• 160/84 mmHg
• Once confirmed, treatment SHOULD be initiated
• Lifestyle modification recommended
• Isolated Systolic Hypertension

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CHD Death according to SBP and DBP in MRFIT
(n350,000)
Systolic blood pressure Diastolic blood pressure
Relative risk of CHD mortality
Decile
lt112lt71
112-71-
118-76-
121-79-
125-81-
129-84-
132-86-
137-89-
142-92-
gt151gt98
SBP
DBP
He J, et at. Am Heart J. 1999138211-219.
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Stroke Death According to SBP and DBP in MRFIT
(n350,000)
Systolic blood pressure Diastolic blood pressure
Relative risk of stroke death
lt112lt71
112-71-
118-76-
121-79-
125-81-
129-84-
132-86-
137-89-
142-92-
gt151gt98
SBP
DBP
He J, et at. Am Heart J. 1999138211-219.
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Isolated Systolic Hypertension and Cardiovascular
Disease Risk in Framingham
2.5
ISH BP ?160/lt95 mmHg BP lt140/95 mmHg
82
2.4
Age-adjusted annual CVD event rate per 1000
43
33
18
Men
Women
Plt0.001 for difference between both men and women
with ISH and blood pressure (BP) lt140/95 mmHg
Wilking SV et al. JAMA. 19882603451-3455.
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CLINICAL PEARL

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

26

• Israel takes West Bank and Sinai in six day war
• Beatles release Magical Mystery Tour

1967

• 55 yo male presents to you with BP 192/120 mmHg
• What does this mean ?
• Can this be treated ?

27
The VA Cooperative Study 1967
Cohort 143 men
Mean age 51 years
Eligibility Diastolic BP 115-129 mmHg
Design Double blind placebo control
Therapy HCTZ, reserpine, hydralazine
Duration 1.5 years
BP change -43/30 mmHg
HCTZhydrochlorothiazide
VA Cooperative Study Group. JAMA.
19672021028-1034.
www.hypertensiononline.org
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The VA Cooperative Study 1967

• Terminated Prematurely !
• Excessive deaths in PLACEBO group
• Proved that treatment of severe hypertension was
  beneficial.
• No further placebo controlled studies in severe HT

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How low to treat ?
30
Is there a J-Curve ?


CV Disease
? risk
0 mmHg Blood Pressure 200 mmHg
31
Is there a J-Curve ?


CV Disease
? risk
0 mmHg Blood Pressure 200 mmHg
32
Evidence for J-curve

• BP 0 mmHg gt patient is dead
• Overwhelming evidence now that our BP targets
  should be much lower.

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TREATING TO TARGETHow low should our BP targets
be ?Do we achieve BP targets in treatment of
hypertension ?
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HOT - Target blood pressure is an achievable goal
( patients reaching target)
DBP mm Hg
105
target 80 mm Hg
100
target 85 mm Hg
target 90 mm Hg
95
90
74
60
85
86
73
43
55
80
0
0
3
6
12
24
36
Finalfollow-up
Months
Hansson et al 1998
36
Risk of a major cardiovascular event reduced by
30 in the HOT Study
Achieved DBPmm Hg
105
100
95
90
85
80
0
5
Optimal DBPreduction in theHOT Study
10
15
20
25
30
risk reduction
Hansson et al 1998
37
Significant benefits from intensive blood
pressure reduction in diabetics
Major CV events/1000 patient years
25
20
15
p0.005 for trend
10
5
0
90
85
80
mm HgTarget DBP
Hansson et al 1998
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HOT - Combination therapy needed to achieve
target blood pressure
Enrolment
Final
59
32
Monotherapy
Combinationtherapy
SBP/DBPmm Hg
161/98
142/83
80 mm Hg
85 mm Hg
90 mm Hg
26
32
37
SBP/DBPmm Hg
140/81
142/83
144/85
Hansson et al 1998
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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 gt 50-80 subjects

HOT Study Group. Lancet. 1998351(9118)1755-1762.
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Heart Foundation Guidelines 2004

• Targets
• Adults gt 65 lt 140/90 mmHg
• All others lt130/85 mmHg
• Proteinuria gt 1g lt 125/75 mmHg
• MOST of your patients will require combined
  therapy

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Randomized Design of ALLHAT BP Trial
42,418 High-risk hypertensive patients
Consent / Randomize
Amlodipine Chlorthalidone Doxazosin Lisinopril
Follow until death or end of study (4-8 years,
mean 4.9 years)
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Inclusion Criteria

• Men and women aged gt 55 years
• Seated blood pressure (2 categories)
• 1) Treated for _at_ least 2 months.
• 2) Not on drugs or on drugs lt 2 months.
• Additional risk factor or target organ damage.

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Blood Pressure Control
Cushman, et al. J Clinical Hypertens 2002
4393-404
44
CLINICAL PEARL 2

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

45
ALLHAT Treatment and Blood Pressure Control
1 Drug
2 Drugs
?3 Drugs
2.0
1.7
1.4
1.3
Patients ()
Average of drugs
6 mos
1 yr
3 yr
5 yr
Blood pressure controlled lt140/90 mmHg Blood pressure controlled lt140/90 mmHg Blood pressure controlled lt140/90 mmHg Blood pressure controlled lt140/90 mmHg
49.8 55.2 62.3 65.6
Cushman WC, et al. J Clin Hypertens.
20024393-405.
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Proportion of Uncontrolled ALLHAT Participants
Not Stepped Up at Annual Visits
Cushman, et al. J Clinical Hypertens 2002
4393-404
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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.

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Hypertension Target BP !(lt160/95, lt140/90)
20
18
16
6
34
9
2.5
19
JNC VI. Arch Int Med 19971572413Colhourn et
al. J Hypertens 199816747Marques-Vidal et al.
J Hum Hypertens 199711213
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Heart Foundation Guidelines 2004

• Targets
• Adults gt 65 lt 140/90 mmHg
• All others lt130/85 mmHg
• Proteinuria gt 1g lt 125/75 mmHg
• MOST of your patients will require combined
  therapy

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How do we get blood pressure under control ?
52

• Non-pharmacological Measures
• Pharmacotherapy

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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 lt 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
54
Dietary Approaches to Stop Hypertension (DASH)
Study

• Published 1997 NEJM
• N459
• DBP 80-95 mmHg
• SBP lt 160 mmHg
• 8 weeks

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DASH Study - design

• control diet
• v
• fruit/vegetable rich diet
• v
• combination diet

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Results (n133)
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DASH Results (n133)

• 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

58
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 lt 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
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Which Drugs to Use?
60
ALLHAT Mean Systolic and Diastolic Blood Pressure
During Follow-up
Chlorthalidone
Chlorthalidone
Amlodipine
Amlodipine
Lisinopril
Lisinopril
Compared to chlorthalidone SBP significantly
higher in amlodipine (1 mmHg) and lisinopril (2
mmHg) groups.
Compared to chlorthalidone DBP significantly
lower in amlodipine group (1 mmHg).
Systolic BP (mmHg)
Diastolic BP (mmHg)
0
1
2
3
4
5
6
0
1
2
3
4
5
6
Follow-up, yrs
ALLHAT Research Group. JAMA. 20022882981-2997.
61
ALLHAT Primary Outcome Cumulative fatal CHD and
non-fatal MI
Chlorthalidone
Amlodipine
Lisinopril
Cumulative Fatal CHD and Nonfatal MI event rate
()
0
1
2
3
4
5
6
7
Time to event (yrs)
ALLHAT Research Group. JAMA. 20022882981-2997.
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ALLHAT Stroke by Treatment Group
Chlorthalidone
Amlodipine
Lisinopril
Cumulative event rate ()
0
1
2
3
4
5
6
7
Time to event, yrs
ALLHAT Research Group. JAMA. 20022882981-2997.
63
ALLHAT Heart Failure by Treatment Group
Plt0.001 for chlorthalidone vs amlodipine and
chlorthalidone vs lisinopril
Chlorthalidone
Amlodipine
Lisinopril
Cumulative event rate ()
0
1
2
3
4
5
6
7
Time to event, yrs
ALLHAT Research Group. JAMA. 20022882981-2997.
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Special Groups

• JNC VII

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ANPB2 ACEI v thiazide

• 65-84 yrs both sexes
• gt 160 systolic OR gt 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 gt 20 sys. and gt 10 dias. fall to
• lt 160/90 (140/80 mmHg if tolerated)
• Family practices

Wing L et al 2003 NEJM
66
ANBP2 - BP after Randomisation
67
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

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ANBP2 Primary endpoints
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ANBP2 Conclusions

• Cardiac - ACEI gt diuretics
• Stroke - diuretics gt 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 ..

70
Blood Pressure Lowering Treatment Triallists
Collaboration

• N162,341
• Overview of 29 RCTs
• Effects of Different Blood Pressure Lowering
  Regimens on Major Cardiovascular Events
• Trials including ACEI, CCBs, ARBs, b-blockers,
  diuretics

BPLTTC Lancet 2002. 3621537-35
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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

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• 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
73

• 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)

74

• STUDIES COMPARING DRUG CLASSES
• Stroke
• Borderline significance ? ACEI inferior to D/BB
  and CCB
• CHD
• No difference between ACEI, D/BB and CCB
• CHF
• ACEI and D/BB superior to CCB
• Major CV Events
• No differences
• CV Death
• No differences
• Total Mortality
• No differences

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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

77
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.

78
VALUE Study
Valsartan Antihypertensive Long-Term Use
Evaluation2004
79
VALUE 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
• N15,000

Mann J, Julius S. Blood Press. 19987176183.
80
Effects of Angiotensin II at AT1 and AT2 Receptors
AT2
AT1
Blocked by ARBs

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

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

Siragy H. Am J Cardiol. 1999843S8S.
81
VALUE Systolic Blood Pressure in Study
Sitting SBP by Time and Treatment Group
155
Valsartan (N 7649)
Amlodipine (N 7596)
150
mmHg
145
140
135
1
24
48
2
3
4
6
12
18
30
36
42
54
60
66
Baseline
Months
(or final visit)
Difference in SBP Between Valsartan and Amlodipine
5.0
4.0
3.0
2.0
mmHg
1.0
0
1
24
48
2
3
4
6
12
18
30
36
42
54
60
66
1.0
Months
(or final visit)
Julius S et al. Lancet. June 2004363.
82
VALUE Diastolic Blood Pressure in Study
Sitting DBP by Time and Treatment Group
90
Valsartan (N 7649)
Amlodipine (N 7596)
mmHg
85
80
75
Baseline
1
24
48
2
3
4
6
12
18
30
36
42
54
60
66
Months
(or final visit)
Difference in DBP Between Valsartan and Amlodipine
5.0
4.0
3.0
mmHg
2.0
1.0
0
1
24
48
2
3
4
6
12
18
30
36
42
54
60
66
1.0
(or final visit)
Months
Julius S et al. Lancet. June 2004363.
83
VALUE Primary Composite Cardiac Endpoint
14 12 10 8 6 4 2 0
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event ()
HR 1.03 95 CI 0.941.14 P 0.49
0 6 12 18 24 30 36 42 48 54 60 66
Time (months)
Number at risk
7649
7459
7407
7250
7085
6732
6906
6536
5911
3765
1474
6349
Valsartan
Amlodipine
7596
7469
7424
7267
7117
6772
6955
6576
5959
3725
1474
6391
Julius S et al. Lancet. June 2004363.
84
VALUE Fatal and Non-fatal Stroke
6 5 4 3 2 1 0
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event ()
HR 1.15 95 CI 0.981.35 P 0.08
0 6 12 18 24 30 36 42 48 54 60 66
Time (months)
Number at risk
Valsartan
7649
7494
7448
7312
7170
6877
7022
6692
6093
3859
1516
6515
7596
Amlodipine
7499
7455
7334
7195
6918
7055
6744
6163
3846
1532
6587
Julius S et al. Lancet. June 2004363.
85
VALUE Fatal and Non-FatalMyocardial Infarction
7 6 5 4 3 2 1 0
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event ()
HR 1.19 95 CI 1.02-1.38 P 0.02
0 6 12 18 24 30 36 42 48 54 60 66
Time (months)
Number at risk
7649
7499
7458
7319
7177
6853
7016
6680
6078
3864
1520
6504
Valsartan
Amlodipine
7596
7497
7458
7332
7205
6905
7065
6727
6141
3840
1532
6562
Julius S et al. Lancet. June 2004363.
86
VALUE Heart Failure
Hospitalisation for HF or death from HF
9 8 7 6 5 4 3 2 1 0
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event ()
HR 0.89 95 CI 0.77-1.03 P 0.12
0 6 12 18 24 30 36 42 48 54 60 66
Time (months)
Number at risk
Valsartan
7649
7485
7444
7312
7169
6852
7012
6671
6072
3860
1513
6498
Amlodipine
7596
7486
7444
7312
7176
6874
7033
6702
6100
3823
1511
6534
Julius S et al. Lancet. June 2004363.
87
VALUE Incidence of New-onset Diabetes
23 Risk Reduction With Valsartan
18
P lt 0.0001
16
14
12
10
New-Onset Diabetes ( of patients in treatment
group)
16.4
8
13.1
6
4
2
0
Valsartan-based Regimen (n 5254)
Amlodipine-based Regimen (n 5168)
Julius S et al. Lancet. June 2004363.
88
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

Julius S et al. Lancet. June 2004363.
89
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.
• n25,000, HOPE-like patients
• Recruitment completed July 2003
• Follow up 3.5-5 yrs

90
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
• N5700 (/6000)
• Follow up 3.5-5 yrs

91
SECONDARY HYPERTENSIONNew Screening Tests

• George Mangos
• DEPARTMENT OF MEDICINEST GEORGE HOSPITAL
• UNSW

92
Causes of Secondary Hypertension

• Renal Artery Stenosis
• Phaeochromocytoma
• Primary Aldosteronism
• Alcohol Excess
• Obesity
• Cushings Disease
• Low Aldo / Low Renin syndromes

93
New screening tests for hypertension

• Sensitivity ability of a test to detect a true
  positive
• Specificity ability of a test to detect true
  negative

94
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

95
Renal Artery Stenosis

• Atherosclerotic RAS
• Fibromuscular Hyperplasia
• Takayasus 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 angioplastystenting of a-s RAS

Zierler 2003 Mayo Proceedings
96
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
97
Doppler US diagnosis of RAS

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

98
Contrast enhanced sonography in the diagnosis of
renal artery stenosisArgalie 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

99
Contrast enhanced sonography in the diagnosis of
renal artery stenosisArgalie et al Radiologica
Medica 2004

• Correcting for excluded patients
• Sensitivity 50 (colour doppler) 80 (power
  doppler)

100
Captopril Renal Scan

• Sensitivity 84-100
• Specificity 62-100
• Strengths
• Functional Test
• Relatively Non-Invasive
• Weaknesses
• Less sensitive if CRF present
• Cant be taking an ARB or ACEI

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CT Angiography

• Sensitivity gt 90
• Specificity gt 90
• Problems
• Contrast (often gt 100 mls)
• Accessory arteries not well seen
• Ca affects stenosis interpretation
• Compared favourably to US (Halpern 1998)
• Sensitivity 96 v 63

102
MR Angiography

• Sensitivity 97 (c/w 69 US)
• Specificity gt 95 (Qanadli 2001)
• Problems
• Availability cost
• Metallic implants
• Co-operation, breath-holding and claustraphobia

103
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

104
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)

105
Catecholamine metabolism
106
Test Comparisons
Test Sensitivity Specificity
Plasma Metanephrines 97 85
24hr U total metanephrines catecholamines 90 98
Sawka et al, JCEM, 2003
107
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
108
Testing for Phaeochromocytoma
109
Metanephrine Summary

• Tumours usually show levels gt x3-4 normal
• Specificity about 85, 15 false positives
  (usually lt 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

110
Rule of 10s

• Phaeochromocytoma
• 10 extraadrenal
• 10 extraabdominal
• 10 malignant
• 10 bilateral
• 10 hereditary

Dluhy RG, 2002, NEJM
111
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.
112
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
113

• THANK YOU
• Dr Peter Campbell team
• Daya Naidoo (SEALS)

114
Captopril Renal Scan

• Nuclear Scan
• Renal scan pre-post captopril
• Efferent arteriole constricted in RAS to maintain
  GFR
• Captopril dilates efferent arteriole causing fall
  in GFR in RAS kidney

115
Captopril Renal Scan

• Strengths
• Functional Test
• Relatively Non-Invasive
• Weaknesses
• Less sensitive if CRF present
• Cant be taking an ARB or ACEI

116
www.med.unsw.edu.au/stgrenal
117
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

118
(No Transcript)
119
Aldosteronerenin ratio

• Aldosterone renin ratio
• Normal range ?
• Interfered with by drugs
• False positive b blockers
• False negative ACEI, Ca antagonists, diuretics
• Suspension of medication difficult

120
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

121
FH-1
122
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
123
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