Blood pressure reduction with statins
Meta-analysis of randomised controlled trials
P. Strazzullo1, S.M. Kerry2, A. Barbato1,2,
M. Versiero1, L. D’Elia1 & F.P. Cappuccio3
1
Department of Clinical & Experimental Medicine, Federico II Medical School, University of
Naples, Italy; 2 Division of Community Health Sciences, St George’s University of London, UK;
3 Clinical Sciences Research Institute, Warwick Medical School, Coventry, UK
Conflict of Interest
• FPC has received honoraria and refund
of expenses from Pfizer
2
Background
•
•
•
•
Possible anti-HPT effect of statins investigated by very few
studies in patients with HPT and hypercholesterolemia.
Additional information from several other studies, not
specifically aimed at the evaluation of the statins’ anti-HPT
effect.
Present knowledge hampered by severe limitations
(inadequate design, small sample size, too short Rx
period, modification of concomitant anti-HPT Rx during the
trial).
Nevertheless, effect of statins on BP plausible given their
impact on endothelial function, interaction with RAS and
influence on large artery compliance.
3
Objectives
• To carry out a systematic review of the
literature to identify all studies reporting BP
data during treatment with statins.
• To carry out a meta-analysis of the effect of
statins on BP including all trials which met
strict predefined inclusion criteria.
4
Design and Methods
• Meta-analysis of randomised controlled trials
comparing statins vs placebo (or control)
• Medline (1966 to Oct 2005), Embase (1980 to Oct
2005), Databases (Cochrane, Clinical Effectiveness,
HTA, NHS Economic Evaluation, TRIP, CRD, AHRQ)
identified 175 trials.
5
Flow Diagram
RCTs identified
(n=175)
RCTs retrieved
(n=156)
No control group
(n=19)
BP treatment
not constant
(n=26)
Incomplete data
(n=97)
Other (n=13)
RCTs suitable
(n=20)
RCTs included
(n=20)
Placebo-controlled (n=20)
High TC pts (n=19)
High BP pts (n=11)
Pravastatin (n=8) Simvastatin (n=6) Fluvastatin (n=3)
Atorvastatin, Cerivastatin (n=2) Lovastatin (n=1)
6
Design and Methods
• Meta-analysis of randomised controlled trials
comparing statins vs placebo (or control)
• Medline (1966 to Jan 2003), Embase (1980 to Jan
2003), Databases (Cochrane, Clinical
Effectiveness, HTA, NHS Economic Evaluation,
TRIP, CRD, AHRQ) identified 175 potential trials
• Outcome measures: difference in SBP and DBP
between patients taking statins and those taking
placebo (or control Rx)
• 889 patients studied (324 on statins, 303 on
Control, 262 in cross-over trials, age 41-70 yrs)
• Duration: from 4 weeks to 1 year
7
Statistical Analysis
• Random effects model
• Difference in BP (95% CI)
• Publication bias by funnel plot and
Egger’s test
• ‘Trim and fill’ method
• Heterogeneity by chi-square
• Meta-regression to assess the possible
association of the BP effect of statin with
age, baseline BP, duration, HPT status,
T2D, TChol response to statin
8
Effect of Statins on Systolic BP
STATIN better
CONTROL better
McDowell,1991
Hommel,1992
O'Callaghan,1994
Bak (1),1998
Bak (2),1998
Nakamura,2001
Lee,2002
De Rosa(1),2003
De Rosa(2),2003
Jenkins,2003
Balletshofer,2005
Kool,1995
Straznicky,1995
Tonolo,1997
Glorioso,1999
Shige,2001
Ferrier,2002
Fogari ,2004
Ikeda,2004
Koh,2004
-4.0 ( -19.1,11.1)
-8.0 ( -25.5,9.5)
0.0 ( -14.7,14.7)
1.9( -4.8,8.6)
-2.3 ( -8.8, 4.2)
-6.0 ( -13.0,1.0)
-1.0 ( -6.5,4.5)
-2.0 ( -9.5,5.5)
-3.0 ( -10.4,4.4)
5.2 ( -2.7,13.1)
-10.0 ( -21.8,1.8)
3.0 ( -4.3,10.3)
0.5 ( -4.0, 5.0)
0.0 ( -2.0,2. 0)
-7.0 ( -10.0, -4.0)
1.0 ( -5.6,7.6)
-6.0 ( -11.1, -0.9)
-4.2 ( -7.3,1.1)
-4.9 ( -7.2, -2.6)
5.0 (0.2,9.9)
-1.9 (-3.8 ÷ -0.1)
Combined
-20
Heterogeneity p<0.01
0
Intervention effect (mmHg)
20
40
9
Effect of Statins on Diastolic BP
STATIN better
CONTROL better
McDowell,1991
Hommel,1992
O'Callaghan,1994
Bak (1),1998
Bak (2),1998
Nakamura,2001
Lee,2002
De Rosa(1),2003
De Rosa(2),2003
Jenkins,2003
Balletshofer,2005
Kool,1995
Straznicky,1995
Tonolo,1997
Glorioso,1999
Shige,2001
Ferrier,2002
Fogar i,2004
-6.0 ( -14.2,2.2)
-5.0 ( -14.9,4.9)
4.0 ( -2.9,10.9)
1.1 ( -2.1,4.3)
-1.0 ( -4.2,2.2)
-2.0 ( -7.3,3.3)
-1.0 ( -3.8,1.8)
-2.0( -7.2,3.2)
-2.0 ( -7.1,3.1)
-0.9 ( -6.0,4.2)
-5.0 ( -11.3,1.3)
1.0 ( -3.1,5.1)
1.0 ( -2.0,4. 0)
-0.5 ( -1.7,0.7)
-4.0 ( -6.0, -2.0)
1.0 ( -1.8,3.8)
-2.0 ( -4.0, -0.0)
-3.4 ( -4.7, -2.1)
-0.2 ( -2.2,1.8)
4.0 (1.0,7.0)
Ikeda,2004
Koh,2004
- 0.9 (- 2.0 ÷ 0.2)
Combined
-10
Heterogeneity p<0.01
0
Intervention effect (mmHg)
10
20
10
Funnel plots for systolic and diastolic BP
Diastolic blood pressure
Systolic blood pressure
Egger’s test, p=0.48
Egger’s test, p=0.58
2
1/SE (intervention effect)
1/SE (intervention effect)
1
0.5
0
1.5
1
0.5
0
-10
-5
0
5
Intervention effect (mmHg)
-10
-5
0
Intervention effect (mmHg)
5
11
Effect of Statins on Systolic BP in studies with
average baseline BP >130 mmHg
STATIN better
CONTROL better
McDowell,1991
-4.0 (-19.1,11.1)
Hommel,1992
-8.0 (-25.5,9.5)
O'Callaghan,1994
0.0 (-14.7,14.7)
Bak (1),1998
1.9 (-4.8,8.6)
Bak (2),1998
-2.3 (-8.8, 4.2)
De Rosa(1),2003
-2.0 (-9.5,5.5)
De Rosa(2),2003
-3.0 (10.4,-4.4)
Balletshofer,2005
-10.0 (-21.8,1.8)
0.5 (-4.0, 5.0)
Straznicky,1995
Glorioso,1999
-7.0 (-10.0,-4.0)
Ferr
ier,2002
-6.0 (-11.1,-0.9)
-4.9 (-7.2,-2.6)
Ikeda,2004
-4.0 (-5.8 ÷ -2.2)
Combined
-20
Heterogeneity p=0.26
0
20
Intervention effect (mmHg)
40
12
Effect of Statins on Diastolic BP in studies with
average baseline BP >80 mmHg
STATIN better
CONTROL better
Hommel,1992
-5.0 ( -14.9,4.9)
O'Callaghan,1994
4.0 ( -2.9,10.9)
Bak (1),1998
1.1 ( -2.1,4.3)
Bak (2),1998
-1.0 ( -4.2,2.2)
De Rosa(1),2003
-2.0 ( -7.2,3.2)
De Rosa(2),2003
-2.0 ( -7. 1,3.1)
-5.0 ( -11.3,1.3)
Balletshofer,2005
1.0 ( -2.0,4.0)
Straznicky,1995
-4.0 (-6.0,-2.0)
Glorioso,1999
-2.0 (-4.0,0.1)
Ferri er,2002
-0.2 (-2-2,1.8)
Ikeda,2004
-1.2 (- 2.6 ÷ 0.1)
Combined
- 10
0
10
Intervention effect (mmHg)
Heterogeneity p=0.069
20
13
Meta-regression of intervention effect on
systolic and diastolic BP
(p=0.023)
Intervention effect (DBP)
Intervention effect (SBP)
(p=0.066)
5
0
-5
55
00
-5
-5
-10
120
130
140
150
Average baseline systolic BP (mmHg)
160
70
80
90
100
Average baseline diastolic BP (mmHg)
14
Limitations
•
•
•
•
•
•
•
Small n° of studies, small total sample size.
Much larger studies not included to avoid
potential bias of BP treatment (e.g. WOSCOPS,
ASCOT, ALLHAT, etc)
Between-studies heterogeneity.
Most studies NOT specifically designed to
evaluate the effect of statins on BP.
Most studies carried out in hypercholesterolemic
patients.
Publication bias impossible to rule out completely.
Intra-class differences not discernible.
15
Summary and Conclusions
• Small but statistically significant effect of statins on
BP, more prominent on systolic BP
• Effect greater in those with higher baseline BP, BUT
unrelated to age, duration of treatment, BP Rx, T2D
and cholesterol response,
• Class effect difficult to detect
• Possible mechanisms – increased NO bioavailability,
reduced ET1 production, improved endothelial
function, inhibition of ROS production, reduction in
large arteries stiffness, improved systemic arterial
compliance, down-regulation of AII type 1 receptor
and reduced vasoconstrictor response to AII.
• Potential importance for controlling high BP in
patients with CV co-morbidities
16