Lacidipine: Summary of potential antiatherosclerotic mechanisms

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

2. ELSA: Inclusion and exclusion criteria • Major inclusion criteria • Aged 45–75 years • Systolic and diastolic blood pressure of 150–210 mmHg and 95–115 mmHg, respectively • Readable ultrasound carotid artery scan with maximum intima-media thickness (IMT) < 4.0 mm • Major exclusion criteria • Fasting serum cholesterol > 320 mg/dL • Insulin-dependent diabetes mellitus • Myocardial infarction (within previous 12 months) • Stroke (within previous 6 months) • Previous carotid endarterectomy

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

4. Measurement of IMT and CBMmax • The primary endpoint for IMT measurement in the ELSA trial is CBMmax. 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 Internal carotid Stratification Location Plaque: 1.3 mm Internal Bifurcation Thickening: 1.0, <1.3 mm Common Normal: <1.0 mm Common carotid Zanchetti et al., 1998

5. Study endpoints • Primary objective • Comparison of effects of lacidipine and atenolol on carotid IMT • Primary efficacy outcome • Change in CBMmax • Secondary objective • Comparison of the effects of lacidipine and atenolol on: • cardiovascular events • blood pressure control • progression/regression of atherosclerotic plaques • Secondary efficacy outcomes • Percentage of patients with increased/decreased number of carotid plaques • Incidence of fatal/non-fatal ‘major’ and ‘minor’ cardiovascular events, and total mortality • Change in mean maximum IMT (Mmax)

6. Baseline characteristics Variable Lacidipine Atenolol 56.1 ± 7.5 55.9 ± 7.5 Age (years) Gender (% males) 54.2 55.4 Current smoking (%) 22.6 18.4 Body mass index (kg/m2) 27.2 ± 3.9 27.2 ± 3.6 Total cholesterol (mmol/L)) 5.80 ± 0.98 5.84 ± 1.01 Serum HDL-cholesterol (mmol/l) 1.34 ± 0.43 1.34 ± 0.46 Serum LDL-cholesterol (mmol/l) 3.70 ± 0.94 3.73 ± 0.98 Serum triglycerides (mmol/l) 1.51 ± 0.71 1.51 ± 0.77 Clinic DBP (mmHg) 101.4 ± 5.3 101.3 ± 4.9 Clinic SBP (mmHg) 163.9 ± 12.2 163.1 ± 12.5 24-h ambulatory DBP (mmHg) 88.2 ± 9.3 87.6 ± 9.3 24-h ambulatory SBP (mmHg) 141.4 ± 14.0 140.4 ± 14.2 CBMmax(mm) 1.1589 ± 0.2399 1.1619 ± 0.2480 IMT-common carotid(mm) 1.0090 ± 0.1980 1.0173 ± 0.2152 IMT-carotid bifurcation(mm) 1.3131 ± 0.3594 1.3115 ± 0.3782

7. Treatment-related changes:Carotid wall CBMmax CBMmax: Final vs. baseline scan 0.06 0.05 0.04 Atenolol Mean change (mm/year) 0.03 Lacidipine 0.02 0.01 0 ITT PP1 PP2 Completers Ratio of mean changes (95% CI) ITT PP1 PP2 Completers 0.2 0.4 0.6 0.8 1 1.2 1.4 In favour of lacidipine In favour of atenolol

8. 1 20 123 515 220 50 8 144 515 278 3 18 170 525 194 34 3 191 525 231 Treatment-related changes: Carotid plaque prevalence Changes in number of carotid plaques per patient from baseline to end of study with lacidipine and atenolol 60 Atenolol 50 Lacidipine 40 % of patients 30 20 10 0 -3 -2 -1 0 +1 +2 +3 Less No change More Change in number of plaques Atenolol (N = 937) Lacidipine (N = 947)

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

10. Safety analysis Relative risk of adverse events in lacidipine- and atenolol-treated patients Events (N) Relative risk (95% CI) Atenolol Lacidipine Myocardial infarction 17 18 Stroke 14 9 Major CV events 33 27 CV death 8 4 All death 17 13 Hospitalised angina 11 17 Other minor CV events 30 27 All serious AEs 201 186 0.1 0.2 0.3 0.5 1.0 2.0 4.0 Lacidipine better Atenolol better

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 CBMmax progression by • 0.0227 mm (ITT population) • 0.0281 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