ELSAThe European Lacidipine Study on Atherosclerosis

Principal Results

Relationship of hypertension and atherosclerosis

Hypertension

Increased turbulent flow(particularly at

bifurcation points)

Increased risk of atherosclerotic

lesions

Mechanical stress of high blood pressure

Endothelial damage

Increased permeability for lipids and free radicals

Release of vasoconstrictive

factors (endothelin)

Zanchetti, 1992

The atherosclerotic process

Monocytes

Endothelium

SMC

Macrophages

Foam cells

Free radicals

Oxidised LDL

-

Circulatingmonocytes

Native LDLEndothelial

injury

Oxygen freeradicals

Native LDL

Smoothmuscle

cell (SMC)

Macrophages

Residentmonocyte/

macrophage

Endothelialcells

Oxygen freeradicals

Oxidativelymodified LDL Foam cell

Oxidativelymodified LDL

Soma et al., 1994

Lacidipine: Dual action against atherosclerotic processes

Macrophage activation/foam cell formation

Oxidation ofLDL cholesterol

Vascular smooth muscle cell migration

Thrombocyte aggregation

Calciumantagonist

Antioxidant

Gaviraghi et al., 1998

Antiatherosclerotic properties of lacidipine: Pre-clinical data (1)

• The antiatherosclerotic activity of lacidipine has been extensively documented in pre-clinical studies, often at non-antihypertensive doses: Lacidipine (0.3, 1.0 and 10 mg/kg/day) completely prevented

arteriolar irregularities in the retina vessel of hypertensive Dahl-S rats; the highest dose was also antihypertensive1

Lacidipine (3 mg/kg/day) reduced carotid intima/media hyperplasia (induced by cuff injury) by approximately 50% in hypercholesterolaemic rabbits2

Lacidipine (0.3 mg/kg/day p.o.) inhibited fatty streak formation in hypercholesterolaemic Golden Syrian hamsters3

Lacidipine inhibited metalloproteinase-9 secretion by human macrophages in culture, an effect expected to stabilise atherosclerotic plaques in vivo4

1Cristofori et al., 1991; 2Soma et al.,1994; 3Cristofori et al., 2000; 4Bellosta et al., 2001

Lacidipine protects stroke-prone hypertensive rats against the impairment of endothelium-dependent vasodilation evoked by a salt-rich diet1

Lacidipine was the most effective of three dihydropyridines in reducing the expression of the endothelial cell adhesion molecules, ICAM-1, VCAM-1 and E-selectin, in response to TNF- stimulation2

Lacidipine (3.0 mg/kg/day) reduced atherosclerotic lesions in the aorta of transgenic apo-E-deficient mice by 50%3

Antiatherosclerotic properties of lacidipine: Pre-clinical data (2)

1Krenek et al., 2001; 2Cominacini et al., 1999; 3Cristofori et al., 2000

Potential antioxidant effects of lacidipine on endothelial function of hypertensive patients

• Several experiments suggest that endothelial dysfunction and reduced nitric oxide (NO)-dependent vasodilation play a key role in atherogenesis

• Essential hypertension reduces responsiveness to endothelium-dependent vasodilators and the suppression of vasodilation by NO synthesis inhibitors

• Lacidipine (4–6 mg/day) but not atenolol (50–100 mg/day) increased endothelium-dependent vasodilation and restored the response to NO synthesis inhibitors

• Markers of oxidative stress, including LDL hydroperoxidases and reactive oxygen species were also reduced by lacidipine

• The antioxidant activity of lacidipine may be a key factor in restoring NO availability and increasing endothelium-dependent vasodilation

Taddei et al., 2001

monocyte

damaged endothelium

macrophage foamcell

lipid

thrombocytes

plaque

oxidative stress

1

2

3

smooth muscle cells 4

5

Gaviraghi et al., 1998

Lacidipine: Summary of potential antiatherosclerotic mechanisms

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

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

12.5mgHCTZ (if required)

6mg

4mg

50mg

100mg

12.5mg25mg

PlaceboAtenolol

Lacidipine

HCTZ (if required)

Clinical examination

Months

Visits

Medication

Measurements

Blood pressure

Trial phases

B-mode ultrasound & arterial blood pressure monitoring

Zanchetti, 1996

Zanchetti et al., 1998

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

Externalcarotid

Commoncarotid

Bifurcation

Internalcarotid

Internal

Common

Thickening: 1.0, <1.3 mm

Plaque: 1.3 mm

Normal: <1.0 mm

Stratification Location

Advantages over other studies

• Large scale gives ELSA statistical power to detect small but clinically significant changes

• Standardisation of techniques for highly reproducible data

• Rigorous quality control for reliable quantification

1Zanchetti et al., 1998; 2Borhani et al., 1996; 3Mancini et al., 2000

ELSA1

MIDAS2

VHAS1

PREVENT3

Number of patients0 500 1000 1500 2000 2500

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)

Patient populations

• Safety, N = 2,334All patients randomised and receiving at least one dose of DB treatment

• Intention to treat (ITT), N = 2,035Patients from the safety population having at least one baseline and one subsequent readable scan

• Per-Protocol 1 (PP1), N = 1,884Patients from the ITT population with no major protocol violations

• Per-Protocol 2 (PP2), N = 1,807Patients from the ITT population with no major protocol violations and with at least one scan after baseline taken under active treatment

• Completers, N = 1,519All PP patients having completed the 4-year DB treatment period

Baseline characteristics

Age (years)

Serum LDL-cholesterol (mmol/l)

Gender (% males)

Serum triglycerides (mmol/l)

Current smoking (%)

Clinic SBP (mmHg)

Body mass index (kg/m2)

CBMmax (mm)

IMT-common carotid (mm)

IMT-carotid bifurcation (mm)

Lacidipine AtenololVariable55.9 ± 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

CBMmax progression – repeated measurements model

Atenolol

Estimated treatment effect (mm):

Lacidipine vs. atenolol

95% Confidence interval

ITT Completers

1006

PP1 PP2

926 901 764

Lacidipine 1022 942 906 765

-0.0227 -0.0276 -0.0293 -0.0281

-0.0330 -0.0381 -0.0399 -0.0394

-0.0124 -0.0171 -0.0187 -0.0167

Patient number:

Statistics (P) < 0.0001 < 0.0001 < 0.0001 < 0.0001

Treatment-related changes:Carotid wall CBMmax

CBMmax: Final vs. baseline scan

Ratio of mean changes (95% CI)

0.02

0.01

0

Mea

n c

han

ge

(mm

/yea

r)

0.06

0.05

0.04

0.03

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

Lacidipine

Atenolol

ITTPP1

PP2

Completers

Treatment-related changes: Common carotid and carotid bifurcation IMT

ITT

PP1

PP2

Completers

Mmax changes in common carotid (CC) and carotid bifurcation (CB) with lacidipine compared with atenolol (repeated measurements model)

CCCB

-0.05 -0.04 -0.03 -0.02 -0.01 0 +0.01

P-values

Treatment Time Baseline Mmax

< 0.0001 < 0.0001 < 0.0001

< 0.0001

< 0.0001

< 0.0001 < 0.0001 < 0.0001

< 0.0001

< 0.0001

< 0.0001 < 0.0001 < 0.0001

< 0.0001 < 0.0001 < 0.0001

< 0.0001 < 0.0001

< 0.0001 < 0.0001

= 0.0085

= 0.0015

= 0.0004

= 0.0013

CCCB

CCCB

CCCB

Estimated lacidipine effect (mm)

Lacidipine better Atenolol better

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 -2 -1 0 +1 +2 +3 Less No change

More

% o

f p

atie

nts

60

50

40

30

20

10

0

Treatment-related changes:Blood pressure and heart rate

-12

-10

-8

-6

-4

-2

0

b/min

SBP DBP HR

-24

-20

-16

-12

-8

-4

0

mmHg

SBP DBP HR

-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

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 death 8

201

18

9

27

4

13

17

27

186

Lacidipine better Atenolol better

1.0

Relative risk (95% CI)

0.1 0.2 0.3 0.5 2.0 4.0

Confirmation of the antiatherosclerotic action of lacidipine

• The ELSA study provides conclusive evidence of the antiatherosclerotic activity of lacidipine

• Lacidipine was more effective than atenolol in slowing progression of carotid wall IMT

• Key features of ELSA that allowed these conclusions included: Measurement techniques Large study size Standardisation of protocol Rigorous quality control

ELSA in the context of previous studies

MIDAS1, VHAS2 and INSIGHT-IMT3

Intervention studies in hypertension All compared the effects of a calcium antagonist and diuretic on carotid IMT All found reductions in IMT with the calcium antagonist similar to those seen with

lacidipine in ELSA Results not as conclusive as in ELSA, because of the limited size of these

studies and the measurement methodology (readings not blind for time-sequence, and IMT measurements limited to the CC)

PREVENT4, BCAPS5 and SECURE6

Placebo-controlled studies in patients with vascular disease All found reductions in CBMmax with antihypertensive therapy

BCAPS demonstrated a reduction in carotid progression with metoprolol,5 suggesting that -blockers also may have a protective effect in preventing atherosclerosis and that the lacidipine effects in ELSA may be over and above those seen with atenolol

1Borhani et al., 1996; 2Zanchetti et al., 1998; 3Simon et al., 2001; 4Pitt et al., 2000; 5Hedblad et al., 2001; 6Lonn et al., 2001

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%

Implications of the ELSA results

• Lacidipine has a greater effect than atenolol in preventing alterations in the carotid wall, despite having a smaller effect on ambulatory blood pressure

• The greater reduction in IMT at the carotid bifurcation over the common carotid supports the antiatherosclerotic activity of lacidipine

• The ELSA results are consistent with the pre-clinical evidence indicating that lacidipine inhibits atherosclerosis at doses insufficient to lower blood pressure

• Therefore, the antiatherosclerotic action of lacidipine appears to be independent of its antihypertensive effects

Clinical significance of the ELSA results

1Hodis et al., 1998; 2Salonen & Salonen, 1993; 3Bots et al., 1997; 4Chambless et al., 2000

• The risk of coronary events or stroke increases progressively with increasing carotid IMT1–4;

• The presence of carotid plaques increases the 5-year risk of myocardial infarction three-fold1;

• The reduction in CBMmax progression seen with lacidipine in the ELSA : 0.009 mm/year difference vs atenolol 40–60% reduction of progression vs atenolol

could reduce the risk of cardiovascular events in the longer term. Increases in IMT progression rate in the same range of those observed with atenolol in ELSA compared to lacidipine have in fact been associated with a 60% greater risk of

myocardial infarction and coronary death1

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