Blood pressure reduction with statins Meta-analysis of randomised controlled trials P. Strazzullo 1, S.M. Kerry 2, A. Barbato 1,2, M. Versiero 1, L. D’Elia 1 & F.P. Cappuccio 3 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.

6 Flow Diagram RCTs 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)

7 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 yrs) Duration: from 4 weeks to 1 year

8 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

9 Effect of Statins on Systolic BP Heterogeneity p<0.01

10 Heterogeneity p<0.01 Effect of Statins on Diastolic BP

11 Funnel plots for systolic and diastolic BP 1/SE (intervention effect) Systolic blood pressure Diastolic blood pressure Intervention effect (mmHg) Intervention effect (mmHg) /SE (intervention effect) Egger’s test, p=0.58 Egger’s test, p=0.48

12 Effect of Statins on Systolic BP in studies with average baseline BP >130 mmHg Heterogeneity p=0.26

13 Effect of Statins on Diastolic BP in studies with average baseline BP >80 mmHg Heterogeneity p=0.069

14 Meta-regression of intervention effect on systolic and diastolic BP

15 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.

16 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