5 Year Risk %

1
Differing influence of hypertension on absolute
and relative risk of stroke and MI
Normotensives
Hypertensives
5 Year Risk ()
20
40
60
80
220
240
260
280
0
100
200
300
120
140
160
180
Systolic Blood Pressure (mmHg)
Brown, M.J. Lancet 2000 355 659 - 660
2
Observational evidence for low threshold in curve
relating treated SBP to incidence of DM related
endpoints in UKPDS
BMJ. 2000 321 412-419
adjusted for age, sex, and ethnic group,
expressed for white men aged 50-54 years at
diagnosis and mean duration of diabetes of 10
years
Updated mean systolic blood pressure
3
Blood Pressure Lowering Treatment Trialists
CollaborationSecond cycle of overview analyses
Turnbull, F. (2003) Lancet 362, 1527-35
4
STROKEComparisons of different active treatments
BP difference (mm Hg)

Favours second listed
Favours first listed

RR (95 CI)
2/0
1.09 (1.00,1.18)
ACE vs. D/BB
1/0
0.93 (0.86,1.01)
CA vs. D/BB
1/1
1.12 (1.01,1.25)
ACE vs. CA
0.5
1.0
2.0
Relative Risk
5
CORONARY HEART DISEASEComparisons of different
active treatments
BP difference (mm Hg)
Favours first listed
Favours second listed


RR (95 CI)
2/0
ACE vs. D/BB
0.98 (0.91,1.05)
1/0
CA vs. D/BB
1.01 (0.94,1.08)
1/1
ACE vs. CA
0.96 (0.88,1.05)
0.5
1.0
2.0
Relative Risk
6
MAJOR CARDIOVASCULAR EVENTS Comparisons of
different active treatments
BP difference (mm Hg)
Favours first listed
Favours second listed


RR (95 CI)
2/0
ACE vs. D/BB
1.02 (0.98,1.07)
1/0
CA vs. D/BB
1.04 (0.99,1.08)
ACE vs. CA
1/1
0.97 (0.92,1.03)
0.5
1.0
2.0
Relative Risk
7
Reduction in CV events in Hypertension Optimal
Treatment (HOT) Study DM vs. non-DM
p0.005 (DM)
Lancet1998 351 175562
8
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9
Benefits of antihypertensive treatment is
proportional to reduction in blood pressure
Results of prospectively-designed overviews of
randomised trials. Lancet 2003 362 1527-35.
10
Coronary Heart Disease
1.50
ACE/CA
1.25
ACE/DBB
Relative risk of CHD
1.00
ACE/plac
CA/DBB
ARB/other
0.75
More/less
0.50
CA/plac
0.25
-10
-8
-6
-4
-2
0
2
4
Systolic blood pressure difference between
randomised groups (mmHg)
11
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12
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13
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14
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15
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16
Target blood pressure new levels for DM
For ambulatory (mean daytime) or home BP
monitoring, reducing these targets by 10/5 is
recommended.
17
BP Thresholds for treatment
18
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19
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20
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21
Drugs acting on therenin-angiotensin
systemBrown MJ. Matching the right drug to the
right patient. Heart 200186113-120.
arteries
Angiotensinogen
AI
AII
Renin
adrenal glands
Aldosterone
kidneys
22
Drugs acting on therenin-angiotensin
systemBrown MJ. Matching the right drug to the
right patient. Heart 200186113-120.
arteries
Angiotensinogen
AI
AII
Renin
adrenal glands
Aldosterone
kidneys
Na
Na
23
Drugs acting on therenin-angiotensin
systemBrown MJ. Matching the right drug to the
right patient. Heart 200186113-120.
arteries
Angiotensinogen
AI
AII
Renin
adrenal glands
Aldosterone
kidneys
24
Design of Rotation

• 56 untreated patients with EHT, aged 21-49
• 8 month, open-label rotation through 4 classes,
  alternating RX and washout
• Drugs Lisinopril 10-20 mg (ACE inhibitor)
• Bisoprolol 5 mg (Beta blocker)
• Dyazide one daily (Diuretic)
• Nifedipine LA 30 mg (Calcium Blocker)
• Best drug repeated at end of rotation

• Evidence of variability
• Number at target higher on best gt first treatment
  
• Lack of correlation between pairs of drugs

25
Influence of rotation on success of monotherapy
ACE INHIBITOR
BETA BLOCKER
CALCIUM BLOCKER
DIURETIC
Dickerson et al. Lancet 3532008-13, 1999
26
Correlations between drug pairs
4 -16 -36
Delta Diastolic Blood Pressure (mmHg)
14 -2 -18
18 -2 -22
-36 -10 12
-18 -2 14
-22 -2 18
-36 -16 4
Delta Diastolic Blood Pressure (mmHg)
27
ADLiB Design

• Double-blind Latin-square placebo-controlled
  randomised crossover rotation through
• Amlodipine 5 mg Calcium blocker
• Doxazosin 4 mg Alpha blocker
• Lisinopril 10 mg ACE inhibitor
• Bisoprolol 5 mg Beta blocker
• Bendrofluazide 2.5 mg Diuretic
• Placebo run-in then 6 x 6 week cycles
• Most effective, best tolerated drug repeated

28
Distribution of best drugs( 24 h BP readings on
these)
135/86
136/89
144/95
154/102
148/99
Amlodipine
Doxazosin
LIsinopril
Bisoprolol
bendrofluazide
29
AB/CD Rule for optimisation of antihypertensive
treatment
AGE
Younger (lt55)
Older (gt55)
Dickerson et al. Lancet 3532008-111999
30
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31
BHS on fixed dose combos

• The UK has by far the lowest rate of fixed-dose
  combination therapy use in Europe and BP control
  rates lag substantially behind those of North
  America.
• All four of the possible permutations of A or
  BC or D have been approved by regulatory
  authorities as fixed-dose combinations.

32
BHS on fixed dose combos

• The most widely used combinations which are
  undoubtedly effective in terms of BP reduction
  are those of ? blockade and thiazide-like
  diuretics, ACE inhibitor or ARB and thiazide-like
  diuretics, and ?-blocker and CCB.
• When fixed-dose combinations replicate the
  desired treatment plan for a patient and when
  there is no cost disadvantage, the BHS recommends
  their use to reduce the number of medications and
  thereby improve adherence with therapy.

33
Probable indications for statin

• All patients up to the age of at least 80 with
  total cholesterol gt3.5 mmol/L and
• active CHD, or
• peripheral arterial disease, or
• history of ischaemic stroke, or
• diabetes, or
• 10 yr CVD risk ? 20

34
Changes in autoregulation in Benign and
Accelerated Hypertension
Hypertensive
Normotensive
Cerebral Blood Flow
Accelerated Hypertension
0 50
100 150 200
DIASTOLIC BLOOD PRESSURE (mm Hg)
Laurence DR, Bennett PN, Brown MJ. Arterial
hypertension, angina pectoris, myocardial
infarction Clinical Pharmacology, 8th Edition,
Churchill Livingston, 1997.
35
Severe Hypertension
Accelerated Hypertension
Urgent Hypertension
36
Summary

• Hypertension is the commonest cause of major
  morbidity, but less than a quarter of patients
  are adequately treated.
• A reduction in cardiovascular disease mortality
  and morbidity can be achieved through improved
  treatment and control of hypertension.
• A greater choice of drugs are available for
  hypertension than for other chronic diseases
• Rational choice of single and combination drugs
  facilitated by understanding their effects on the
  renin system, but systematic trial and error may
  still be necessary