Blood pressure reduction with statinsMeta-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

2

Conflict of Interest

• FPC has received honoraria and refund of expenses from Pfizer

3

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.

4

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.

5

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.

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Flow DiagramRCTs identified

(n=175)

RCTs retrieved(n=156)

RCTs suitable(n=20)

RCTs included(n=20)

No control group (n=19) BP treatment

not constant (n=26)

Incomplete data(n=97)

Other (n=13)

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)

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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

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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

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Effect of Statins on Systolic BP

Heterogeneity p<0.01

Intervention effect (mmHg) -20 0 20 40

Combined

Koh,2004

Ikeda,2004 Fogari ,2004 Ferrier,2002

Shige,2001 Glorioso,1999

Tonolo,1997 Straznicky,1995

Kool,1995 Balletshofer,2005

Jenkins,2003 De Rosa(2),2003 De Rosa(1),2003

Lee,2002 Nakamura,2001

Bak (2),1998

Bak (1),1998 O'Callaghan,1994

Hommel,1992 McDowell,1991 -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)

STATIN better CONTROL better

10Heterogeneity p<0.01

Effect of Statins on Diastolic BP

Intervention effect (mmHg)

-10 0 10 20

Combined

Koh,2004 Ikeda,2004

Fogari,2004

Ferrier,2002

Shige,2001

Glorioso,1999

Tonolo,1997

Straznicky,1995

Kool,1995 Balletshofer,2005

Jenkins,2003

De Rosa(2),2003

De Rosa(1),2003

Lee,2002 Nakamura,2001

Bak (2),1998

Bak (1),1998 O'Callaghan,1994

Hommel,1992

McDowell,1991 -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)

- 0.9 (- 2.0 ÷ 0.2)

STATIN better CONTROL better

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Funnel plots for systolic and diastolic BP 1/

SE

(in

terv

enti

on e

ffec

t)

Systolic blood pressure Diastolic blood pressure

Intervention effect (mmHg)

-10 -5 0 50

0.5

1

Intervention effect (mmHg)

-10 -5 0 50

0.5

1

1.5

2

1/S

E (

inte

rven

tion

eff

ect)

Egger’s test, p=0.58 Egger’s test, p=0.48

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Effect of Statins on Systolic BP in studies with average baseline BP >130 mmHg

Heterogeneity p=0.26

-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)

-2.0 (-9.5,5.5)

-3.0 (10.4,-4.4)

-10.0 (-21.8,1.8)

0.5 (-4.0, 5.0)

-7.0 (-10.0,-4.0)

-6.0 (-11.1,-0.9)

-4.9 (-7.2,-2.6)

Intervention effect (mmHg)

-20 0 20 40

Combined

Ikeda,2004

Ferrier,2002

Glorioso,1999

Straznicky,1995

Balletshofer,2005

De Rosa(2),2003

De Rosa(1),2003

Bak (2),1998

Bak (1),1998

O'Callaghan,1994

Hommel,1992

McDowell,1991

-4.0 (-5.8 ÷ -2.2)

STATIN better CONTROL better

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Effect of Statins on Diastolic BP in studies with average baseline BP >80 mmHg

Heterogeneity p=0.069

STATIN better CONTROL better

Intervention effect (mmHg)

- 10 0 10 20

Combined

Ikeda,2004

Ferri er,2002

Glorioso,1999

Straznicky,1995

Balletshofer,2005

De Rosa(2),2003

De Rosa(1),2003

Bak (2),1998

Bak (1),1998

O'Callaghan,1994

Hommel,1992 -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 ( -7.2,3.2)

-2.0 ( -7. 1,3.1)

-5.0 ( -11.3,1.3)

1.0 ( -2.0,4.0)

-4.0 (-6.0,-2.0)

-2.0 (-4.0,0.1)

-0.2 (-2-2,1.8)

-1.2 (- 2.6 ÷ 0.1)

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Meta-regression of intervention effect on

systolic and diastolic BP

Inte

rven

tion

eff

ect

(SB

P)

Average baseline systolic BP (mmHg)

(p=0.066)

120 130 140 150 160 -10

-5

0

5

Inte

rven

tion

eff

ect

(DB

P)

Average baseline diastolic BP (mmHg)

70 80 90 100

-5

0

5

(p=0.023)

-5

0

5

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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.

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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