Epidemiology and treatment of hypertension

Note the first part of this presentation on risk-based assessment of BP treatment has been provided by Professor Rod Jackson,

Head of Division of Community Health Faculty of Medical & Health Sciences

University of Auckland

Part 1

Defining ‘hypertension’ and making decisions based on cardiovascular risk

Argument

1. There is no clinically relevant entity that can be defined by a mildly raised blood pressure.

2. A mildly raised blood pressure level is not a major determinant of which patients benefit from blood pressure lowering

what is mild hypertension?

SBP (mmHg)

Systolic blood pressure distribution:

Framingham Study participants 35-64 years

74-119 120-139 140-159 160-179 180-300

top x%??

CVD risk by level of systolic blood pressure: 38 year follow-up

Framingham subjects aged 35-64 yrs

0

5

10

15

20

25

30

35

40

45

74-119 120-139 140-159 160-179 180-300

SBP (mmHg)

womenmen

??

Proportion of CVD events by level of systolic blood pressure: 38 year follow-

up Framingham subjects 35-64 yrs

0

5

10

15

20

25

30

35

74-119 120-139 140-159 160-179 180-300

SBP (mmHg)

women % of eventsmen % of events

11

16

26

32

2830

18 17 16

10

??

Proportion of CVD events by level of systolic blood pressure: 38 year follow-

up Framingham subjects aged 35-64 yrs

0

5

10

15

20

25

30

35

74-119 120-139 140-159 160-179 180-300

SBP (mmHg)

0

5

10

15

20

25

30

35

40

45

0

10

20

30

40

50

60

70

35-44 45-54 55-64 65-74 75-84

age group (years)

160 or 100160 or 95150 or 95140 or 90

Definitions of mild hypertension & prevalence

0

10

20

30

40

50

60

70

35-44 45-54 55-64 65-74 75-84

age group (years)

160 or 100160 or 95150 or 95140 or 90

Definitions of mild hypertension & prevalence

?? ≥130/80

what is mild hypertension?

it’s the wrong question

who benefits from blood pressure lowering?

Meta-analysis of RCTs of BP lowering drugs: 15,559 patients, SBP diff 17 mmHg, DBP

diff 9 mmHg, follow-up 4.1 years (≥ 60 years)

Endpoint Odds ratio (Relative risk red.)

Stroke morbidity 35 %

Stroke mortality 36 %

0 0.5 1.0 1.5

CHD mortality 25 %

CHD morbidity 15 %

Insua et al Ann Intern Med 1994;121:355-62

Stroke and blood pressure lowering:subgroup analysis from 17 RCTs

Trial % Events Relative risk red. group control treatment

Some ≥ 110, 6.5 % 4.6 % 32 % all ≤ 115

All entry 2.2 % 1.3 % 39% DBP < 110

0 0.5 1.0 1.5

MacMahon & Rogers J Vasc Med Biol 1993;4:265-71

Some or all 8.2 % 4.7 % 45 % ≥ 115

Stroke and blood pressure lowering:subgroup analysis from 17 RCTs

Trial % Events Odds ratio (Relative risk red.) group control treatment

Older 7.0 % 4.6 % 34 % patients

Younger 2.3 % 1.3 % 43 % patients

0 0.5 1.0 1.5

1º prev. 3.2 % 2.0 % 38 %

2º prev. 27.3 % 18.8 % 38 %

MacMahon & Rogers J Vasc Med Biol 1993;4:265-71

Stroke and blood pressure lowering:subgroup analysis from 17 RCTs

Trial % Events Odds ratio (Relative risk red.) group control treatment

Older 7.0 % 4.6 % 34 % patients

Younger 2.3 % 1.3 % 43 % patients

0 0.5 1.0 1.5

1º prev. 3.2 % 2.0 % 38 %

2º prev. 27.3 % 18.8 % 38 %

MacMahon & Rogers J Vasc Med Biol 1993;4:265-71

1%

2.4%

1.2%

8.5%

which patients should be treated?

“individual treatment can only be justified if there is individual benefit”

“only absolute benefits are relevant to patients”

Relative stroke risk & usual Blood Pressure

0

1

2

3

4

75 81 87 93 98 102

diastolic blood pressure (mmHg)

PSC Lancet 1995;346:1647-53

(45 prospective studies: 450,000 people 13,000 events)

Absolute stroke risk, by age & usual DBP

0

5

10

15

20

75 80 85 90 95 100 105

usual DBP (mmHg)

65 yr +45-64 yr<45 yr

PSC Lancet 1995;346:1647-53

SBP 105 ----189 105 ----189 105 ----189 105 ----189 105 ----189 high chol. - + + + +gluc intol. - - + + +cigarettes - - - + +LVH - - - - +

CVD riskper 1000in 8 years

Absolute risk of CVD risk in 40 year old men by SBP and other risk factors, Framingham, USA

46

210

326

459

700

4 5 6 7 8 4 5 6 7 8

180/105

160/95

140/85

120/75

180/105

160/95

140/85

120/75

180/105

160/95

140/85

120/75

180/105

160/95

140/85

120/75

180/105

160/95

140/85

120/75

180/105

160/95

140/85

120/75

180/105

160/95

140/85

120/75

180/105

160/95

140/85

120/75

4 5 6 7 8 4 5 6 7 8

4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8

Nonsmoker Smoker Nonsmoker Smoker

WOMEN

AGE

70

AGE

50

AGE

40

DiabetesNo Diabetes

Ratio of Total Cholesterol:HDL Ratio of Total Cholesterol:HDL

Ratio of Total Cholesterol:HDL Ratio of Total Cholesterol:HDL

AGE

60

4 5 6 7 8 4 5 6 7 8

180/105

160/95

140/85

120/75

180/105

160/95

140/85

120/75

4 5 6 7 8 4 5 6 7 8

Nonsmoker Smoker Nonsmoker Smoker

AGE

70

DiabetesNo Diabetes

Ratio of Total Cholesterol:HDL Ratio of Total Cholesterol:HDL

CVD risk & NNTs5yr CVD risk 5 yr NNT*

> 30% < 10.5-10% 40

2.5-5% 85

< 2.5% >120

* assumes 33% RRR

50 yr old womanBP 160/95 mmHg non smokerTC 240 mg/dlHDLC 62 mg/dlBMI 25no Hx CVD

60 yr old manBP 148/ 88 mmHgsmokerTC 240 mg/dlHDLC 38 mg/dlBMI 25no Hx CVD

is BP lowering therapy indicated ?

50 yr old womanBP 160/95 mmHg non smokerTC 240 mg/dlHDLC 62 mg/dl

60 yr old manBP 148/ 88 mmHgsmokerTC 240 mg/dlHDLC 38 mg/dl

is BP lowering therapy indicated ?

5 yr absolute CVD risk: 4%5 yr NNT: 72

5 yr absolute CVD risk: 24%5 yr NNT: 12

50/60 yr old womannon smokerTC 240 mmol/LHDLC 60 mmol/LNo diabetes

SBP mmHg: 150 160 1705 yr NNT: 90 / 50 70 / 42 60 / 37

To treat or not to treat “mild hypertension”

“treat risk not blood pressure”

“only absolute risks and benefits are relevant to patients”

“the payer should choose the threshold”

Part 2Pharmacological considerations in

hypertension management

Sue Hill and David Henry

Discipline of Clinical Pharmacology

Factors that influence blood pressure

sympathetic nervous system total peripheral resistance

– mainly arterioles

intravascular volume (renin-angiotensin)– renal excretion

atheroma, thrombosis

things that alter vascular resistance

vascular smooth muscle– mediators from sympathetic nerves and vascular

endothelium– calcium dependent – contraction due to intracellular calcium– relaxation due to calcium entry or cGMP, cAMP

depends on intact endothelium complex, interdependent biochemical

reactions

drugs that will reduce vascular resistance

nitric oxide, nitrates - antagonists - antagonists Calcium channel blockers angiotensin II antagonsists (lots more)

other mechanisms to remember

central control - – methyldopa, ganglion blocking drugs

renal excretion of sodium and water– diuretics, spironolactone

drugs we use for hypertension

- blockers thiazide diuretics Calcium channel blockers angiotensin converting enzyme

inhibitors ( others - alphamethyldopa,

reserpine, hydralazine, prazosin )

thiazide diuretics

ACTION:increase sodium and water excretion by decreasing reabsorption of

sodium and chloride in the distal tubule (later effect on vessels)

EFFECTlowers blood pressure- over several days

decreases complications, morbidity and mortality ( good clinical trials)

Side effects:– metabolic effects: diabetes, gout, low Na, K, impotence

- adrenoceptor antagonists

ACTION: – effects on heart (1) and smooth muscle (2 ) via noradrenaline

– lowers BP: • reduces cardiac output• reduces renin release• reduces central sympathetic activity• effect on pre-synaptic noradrenaline release

– nonselective antagonist = propranolol

– relatively selective 1 = metoprolol, atenolol

– mixed agonist/antagonist - oxprenolol

- adrenoceptor antagonists

EFFECTlowers blood pressure - over several days

decreases complications, mortality and morbidity (good clinical trials)

SIDE EEFECTS– bronchospasm, fatigue, bad dreams, cold

extremities– worsening cardiac failure, heart block– hypoglyacaemia

ACE-inhibitors

ACTION– inhibits conversion of angiotensin I to angiotensin II - effects on

vasculature in kidney , brain, heart– vasodilator– eg: captopril, enalapril, lisinopril, ramipril

EFFECTS– lower blood pressure- relatively rapidly– effect on mortality, morbidity and complications??– Reduces mortality in cardiac failure, post-AMI; good clinical trials

ACE-inhibitors

SIDE EFFECTS:– cough, rash, taste disturbances– renal failure, neutropenia, proteinuria

COST– relatively expensive

Angiotensin II antagonists

losarten, ibersarten, candesarten actions similar to ACE inhibitors effects

– lower blood pressure- relatively rapidly– effects on clinical outcomes?

Side effects:– rash, cough

cost: expensive

calcium antagonists

ACTION:– three classes: verapamil, dihydropyridines, benzothiazepines

– block calcium entry into cells by preventing opening of voltage gated calcium channels

– act on heart and smooth muscle, depending on type

– vasodilator effect (mainly dihydropyridines)

– two forms - immediate and slow release

EFFECTS– lower blood pressure - can be rapid– mortality, morbidity, complications??

Calcium antagonists

SIDE EFFECTS– flushing, headache, ankle swelling, constipation– heart block, worsening cardiac failure

choices

BENEFITS– short-term– long term

RISKS– side-effects– lack of beneficial effect

( unnecessary medication)

issues

Preventive versus curative treatment

need for joint decision making use of drugs with clinical effects

versus elegant pharmacologically active molecules

benefits versus risks!!

terms

agonist, partial agonist receptor antagonist, competitive antagonist ligand affinity mediators tolerance