Blood Pressure Lowering Treatment Trialists Collaboration Second cycle of overview analyses

1
Blood Pressure Lowering Treatment Trialists
CollaborationSecond cycle of overview analyses
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Overview

• Background and aims
• Methods
• Summary of first cycle analyses
• Findings of second cycle analyses
• Interpretation

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Background

• Established in 1995 by the principal
  investigators of ongoing large-scale trials
• To more reliably determine the effects of various
  blood pressure lowering regimens on major
  vascular outcomes and death
• First cycle of analyses published Lancet 2000
  355 1955-64

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Aims
To compare the effects on mortality and major
morbidity of

• Newer blood pressure lowering agents versus
  placebo
• More intensive versus less intensive blood
  pressure lowering regimens
• Blood pressure lowering regimens based on
  different drug classes

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Pre-specified trial eligibility criteria

• Random allocation to
• blood pressure lowering agent versus placebo
• different blood pressure goals
• different blood pressure lowering drugs
• At least 1,000 patients years of follow-up per
  randomised group planned
• Results not available before July 1995

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Pre-specified outcomes

• Primary outcomes
• Stroke
• Coronary heart disease
• Heart failure (fatal or hospitalised)
• Total cardiovascular events (composite of all
  above)
• Cardiovascular mortality
• Total mortality

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Statistical methods

• Analyses by intention-to-treat
• Relative risks combined using fixed effects model
• Each study weighted by inverse of variance
• Overall relative risks and 95 CI calculated
• Chi square tests of homogeneity

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Contributing trials
Second cycle (29 trials, n 162,341)
IDNT INSIGHT JMIC-B LIFE NICOLE NICS-EH NORDIL PAR
T-2 PREVENT PROGRESS
QUIET RENAAL SCAT SCOPE SHELL STOP-2 SYST-EUR UKPD
S-HDS VHAS
AASK ABCD (H) ABCD (N) ALLHAT ANBP2 CAPPP CONVINC
E ELSA HOPE HOT
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ACE inhibitor vs. placebo
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Calcium antagonist vs. placebo
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More intensive vs. less intensive
12
ACE inhibitor vs. diuretic/beta-blocker
13
Calcium antagonist vs. diuretic/beta-blocker
14
ACE inhibitor vs. calcium antagonist
15
STROKEComparisons of active treatments and
control
BP difference (mm Hg)
Favours active
Favours control


RR (95 CI)
-5/-2
0.72 (0.64,0.81)
ACE vs. placebo
-8/-4
0.62 (0.47,0.82)
CA vs. placebo
-4/-3
0.77 (0.63,0.95)
More vs. less
0.5
1.0
2.0
Relative Risk
16
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 (0.86,1.00)
CA vs. D/BB
1/1
1.12 (1.01,1.25)
ACE vs. CA
0.5
1.0
2.0
Relative Risk
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CORONARY HEART DISEASEComparisons of active
treatments and control

BP difference (mm Hg)

Favours active
Favours control
RR (95 CI)
-5/-2
0.80 (0.73,0.88)
ACE vs. placebo
-8/-4
0.78 (0.62,0.99)
CA vs. placebo
-4/-3
More vs. less
0.95 (0.81,1.11)
0.5
1.0
2.0
Relative Risk
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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 (0.88,1.04)
0.5
1.0
2.0
Relative Risk
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HEART FAILUREComparisons of active treatments
and control
BP difference (mm Hg)
Favours active
Favours control


RR (95 CI)
-5/-2
0.82 (0.69,0.98)
ACE vs. placebo
-8/-4
1.21 (0.93,1.58)
CA vs. placebo
-4/-3
0.84 (0.59,1.18)
More vs. less
0.5
1.0
2.0
Relative Risk
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HEART FAILUREComparisons of different active
treatments
BP difference (mm Hg)
Favours first listed
Favours second listed


RR (95 CI)
2/0
ACE vs. D/BB
1.07 (0.96,1.19)
1/0
CA vs. D/BB
1.33 (1.21,1.47)
1/1
ACE vs. CA
0.82 (0.73,0.92)
0.5
1.0
2.0
Relative Risk
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MAJOR CARDIOVASCULAR EVENTSComparisons of active
treatments and control
BP difference (mm Hg)
Favours active
Favours control


RR (95 CI)
-5/-2
ACE vs. placebo
0.78 (0.73,0.83)
-8/-4
0.82 (0.71,0.95)
CA vs. placebo
-4/-3
More vs. less
0.85 (0.76,0.95)
0.5
1.0
2.0
Relative Risk
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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 (1.00,1.09)
ACE vs. CA
1/1
0.97 (0.92,1.03)
0.5
1.0
2.0
Relative Risk
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CARDIOVASCULAR DEATHComparisons of active
treatments and control
BP difference (mm Hg)
Favours active
Favours control


RR (95 CI)
-5/-2
ACE vs. placebo
0.80 (0.71,0.89)
-8/-4
CA vs. placebo
0.78 (0.61,1.00)
-4/-3
More vs. less
0.93 (0.77,1.11)
0.5
1.0
2.0
Relative Risk
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CARDIOVASCULAR DEATHComparisons of different
active treatments
BP difference (mm Hg)
Favours first listed
Favours second listed


RR (95 CI)
2/0
ACE vs. D/BB
1.03 (0.95,1.11)
1/0
CA vs. D/BB
1.05 (0.97,1.13)
1/1
ACE vs. CA
1.03 (0.94,1.13)
0.5
1.0
2.0
Relative Risk
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TOTAL MORTALITYComparisons of active treatments
and control
BP difference (mm Hg)
Favours active
Favours control


RR (95 CI)
-5/-2
ACE vs. placebo
0.88 (0.81,0.96)
-8/-4
CA vs. placebo
0.89 (0.75,1.05)
-4/-3
More vs. less
0.96 (0.84,1.09)
0.5
1.0
2.0
Relative Risk
26
TOTAL MORTALITYComparisons of different active
treatments
BP difference (mm Hg)
Favours first listed
Favours second listed


RR (95 CI)
2/0
ACE vs. D/BB
1.00 (0.95,1.05)
1/0
CA vs. D/BB
0.99 (0.95,1.04)
1/1
ACE vs. CA
1.04 (0.98,1.10)
0.5
1.0
2.0
Relative Risk
27
Angiotensin receptor blocker vs. other
28
Angiotensin receptor blocker vs. other
BP difference (mm Hg)
Favours ARB
Favours other


Outcome
RR (95 CI)
-2/-1
0.79 (0.69,0.90)
Stroke
0.96 (0.85,1.09)
CHD
-2/-1
-2/-1
Heart failure
0.84 (0.72,0.97)
-2/-1
Major CV events
0.90 (0.83,0.96)
CV death
0.96 (0.85,1.08)
-2/-1
Total mortality
0.94 (0.86,1.02)
-2/-1
0.5
1.0
2.0
Relative Risk
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Role of blood pressure reduction

• Are differences in cardiovascular outcomes
  between randomised groups related to observed
  differences in blood pressure?

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Stroke
ACE/CA
ACE/DBB
Relative risk of stroke
ARB/other
ACE/plac
CA/DBB
More/less
CA/plac
Systolic blood pressure difference between
randomised groups (mmHg)
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Stroke
Relative risk of stroke
Systolic blood pressure difference between
randomised groups (mmHg)
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Coronary Heart Disease
1.50
1.25
Relative risk of CHD
1.00
0.75
0.50
0.25
-10
-8
-6
-4
-2
0
2
4
Systolic blood pressure difference between
randomised groups (mmHg)
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Heart Failure
1.50
Relative risk of heart failure
1.25
1.00
0.75
0.50
0.25
-10
-8
-6
-4
-2
0
2
4
Systolic blood pressure difference between
randomised groups (mmHg)
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Major Cardiovascular Events
Relative risk of major CVD
Systolic blood pressure difference between
randomised groups (mmHg)
35
Cardiovascular Deaths
Relative risk of CV death
Systolic blood pressure difference between
randomised groups (mmHg)
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Total mortality
Relative risk of death
Systolic blood pressure difference between
randomised groups (mmHg)
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Conclusions I

• Similar net effects on total cardio-vascular
  events of
• ACE inhibitors
• Calcium antagonists
• Diuretics/beta-blockers
• ARBs also effective in reducing total
  cardiovascular events

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Conclusions II

• ACE-inhibitor- and diuretic/beta-blocker-based
  regimens more effective than calcium antagonists
  for preventing heart failure
• Calcium antagonists may be more effective for
  stroke prevention
• More intensive blood pressure lowering produces
  larger reductions in stroke and total
  cardiovascular events

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Conclusions III

• Size of blood pressure difference between
  randomised groups closely associated with
  reduction in risk (except for heart failure)
• Size of blood pressure reduction appears to be an
  important determinant of outcome

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Acknowledgements

• Collaborating Trialists L Agodoa, C Baigent, H
  Black, JP Boissel, B Brenner, M Brown, C Bulpitt,
  R Byington, J Chalmers, R Collins, J Cutler, B
  Dahlof, B Davis, J Dens, R Estacio, R Fagard, K
  Fox, L Hansson (deceased), R Holman, L Hunsicker,
  J Kostis, K Kuramoto, E Lewis, L H Lindholm, J
  Lubsen, S MacMahon, E Malacco, G Mancia, B Neal,
  C Pepine, M Pfeffer, B Pitt, P Poole-Wilson, G
  Remuzzi, P Ruggenenti, R Schrier, P Sever, P
  Sleight, J Staessen, K Teo, R Turner (deceased),
  P Whelton, L Wing, Y Yui, S Yusuf, A Zanchetti.
  Executive Committee S MacMahon, C Baigent, J
  Cutler, R Fagard, P Whelton, S Yusuf.
  Coordinating Centre C Algert, J Chalmers, N
  Chapman, S MacMahon, B Neal, F Turnbull, M
  Woodward. Financial support Central
  coordination of this project is supported by the
  National Health and Medical Research Council of
  Australia . Thanks also to C Anderson, D
  Catellier, W Elliott, L Elvelin, A Ferraro, G
  Grandits, E Handberg, L Hemphill, J Lanke, H
  Merianos, B Mullane, C Palmer, V Perkovic, J
  Pogue, S Pressel, D Ramjit, C Reid, A Rodgers, I
  Stratton, L Thijs, J Wang, I Warnold and K
  Willson.

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Blood Pressure Lowering Treatment Trialists
CollaborationSecond cycle of overview analyses