1. monocyte damaged endothelium macrophage foam cell lipid thrombocytes plaque oxidative stress 1 2 3 smooth muscle cells 4 5 Gaviraghi et al., 1998 Lacidipine: Summary of potential antiatherosclerotic mechanisms

2. ELSA: Inclusion and exclusion criteria Major inclusion criteria HAged 45–75 years HSystolic and diastolic blood pressure of 150–210 mmHg and 95–115 mmHg, respectively HReadable ultrasound carotid artery scan with maximum intima-media thickness (IMT) < 4.0 mm Major exclusion criteria HFasting serum cholesterol > 320 mg/dL HInsulin-dependent diabetes mellitus HMyocardial infarction (within previous 12 months) HStroke (within previous 6 months) HPrevious carotid endarterectomy

3. Study design 0 1 2 3 Run-in Titration Maintenance -1 0 1 3 4 5 6 7 8 9 10 11 Follow up 6 12 18 24 30 36 42 48 5–9 days 25mg 12.5mg HCTZ (if required) 6mg 4mg 50mg 100mg 12.5mg 25mg Placebo Atenolol Lacidipine HCTZ (if required) Clinical examination Months Visits Medication Measurements Blood pressure Trial phases B-mode ultrasound & arterial blood pressure monitoring Zanchetti, 1996

4. Zanchetti et al., 1998 Measurement of IMT and CBM max The primary endpoint for IMT measurement in the ELSA trial is CBM max. This is defined as the mean of the maximum IMT of the four far walls of the carotid bifurcation and distal common carotid artery External carotid Common carotid Bifurcation Internal carotid Internal Common Thickening:  1.0, <1.3 mm Plaque:  1.3 mm Normal: <1.0 mm StratificationLocation

5. Study endpoints Primary objective HComparison of effects of lacidipine and atenolol on carotid IMT Primary efficacy outcome HChange in CBM max Secondary objective HComparison of the effects of lacidipine and atenolol on: Hcardiovascular events Hblood pressure control Hprogression/regression of atherosclerotic plaques Secondary efficacy outcomes HPercentage of patients with increased/decreased number of carotid plaques HIncidence of fatal/non-fatal ‘major’ and ‘minor’ cardiovascular events, and total mortality HChange in mean maximum IMT (M max )

6. Baseline characteristics Age (years) Serum LDL-cholesterol (mmol/l) Gender (% males) Serum triglycerides (mmol/l) Current smoking (%) Clinic SBP (mmHg) Body mass index (kg/m 2 ) CBM max (mm) IMT-common carotid (mm) IMT-carotid bifurcation (mm) LacidipineAtenololVariable 55.9 ± 7.5 3.73 ± 0.98 55.4 1.51 ± 0.77 18.4 163.1 ± 12.5 27.2 ± 3.6 1.1619 ± 0.2480 1.0173 ± 0.2152 1.3115 ± 0.3782 56.1 ± 7.5 3.70 ± 0.94 54.2 1.51 ± 0.71 22.6 163.9 ± 12.2 27.2 ± 3.9 1.1589 ± 0.2399 1.0090 ± 0.1980 1.3131 ± 0.3594 24-h ambulatory DBP (mmHg)87.6 ± 9.388.2 ± 9.3 Total cholesterol (mmol/L))5.84 ± 1.015.80 ± 0.98 Clinic DBP (mmHg)101.3 ± 4.9101.4 ± 5.3 Serum HDL-cholesterol (mmol/l)1.34 ± 0.461.34 ± 0.43 24-h ambulatory SBP (mmHg)140.4 ± 14.2141.4 ± 14.0

7. Treatment-related changes: Carotid wall CBM max CBM max : Final vs. baseline scan Ratio of mean changes (95% CI) 0.02 0.01 0 Mean change (mm/year) 0.06 0.05 0.04 0.03 ITTPP 1 PP 2 Completers 0.20.40.60.811.21.4 In favour of lacidipineIn favour of atenolol Lacidipine Atenolol ITT PP 1 PP 2 Completers

8. Treatment-related changes: Carotid plaque prevalence Changes in number of carotid plaques per patient from baseline to end of study with lacidipine and atenolol Atenolol (N = 937) Lacidipine (N = 947) 1 3 20 18 123 170 515 525 220 194 50 34 8 3 144 191 515 525 278 231 Lacidipine Atenolol Change in number of plaques -3-20+1+2+3LessNo change More % of patients 60 50 40 30 20 10 0

9. Treatment-related changes: Blood pressure and heart rate -12 -10 -8 -6 -4 -2 0 b/min SBPDBPHR -24 -20 -16 -12 -8 -4 0 mmHg SBPDBPHR -24 -20 -16 -12 -8 -4 0 mmHg -12 -10 -8 -6 -4 -2 0 b/min Blood pressure (SBP, DBP) and heart rate (HR) changes during randomised treatment (ITT) Clinic values 24 h Ambulatory values LacidipineAtenolol

10. Safety analysis Myocardial infarction Relative risk of adverse events in lacidipine- and atenolol-treated patients Stroke All death Hospitalised angina Other minor CV events All serious AEs Events (N) LacidipineAtenolol 17 14 33 17 11 30 Major CV events CV death8 201 18 9 27 4 13 17 27 186 Lacidipine betterAtenolol better 1.0 Relative risk (95% CI) 0.10.20.30.52.04.0

11. Key findings from the ELSA study Compared with atenolol, lacidipine is significantly (P < 0.001) more effective in slowing increases in carotid IMT in hypertensive patients: reduced 4-year CBM max progression by H0.0227 mm (ITT population) H0.0281 mm (Completers population) reduced yearly carotid IMT progression rate by 23– 40% (40–60% in Completers and PP2) increased the proportion of patients with regression of pre-existing plaques by 31%

12. The ELSA study: Summary 4-year, multi-centre study Largest study of treatment effects on carotid IMT to date Careful design and implementation for highly reliable results Clear demonstration of benefits of lacidipine over atenolol in slowing the progression of carotid IMT Clinically significant treatment effect on IMT Verifies pre-clinical evidence of antiatherosclerotic properties of lacidipine Supports antiatherosclerotic actions of lacidipine independent of antihypertensive effects