Lacidipine summary of potential antiatherosclerotic mechanisms
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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. ELSA: Inclusion and exclusion criteria.

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Lacidipine: Summary of potential antiatherosclerotic mechanisms

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Lacidipine summary of potential antiatherosclerotic mechanisms

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


Elsa inclusion and exclusion criteria

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

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


Measurement of imt and cbm max

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


Study endpoints

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)


Baseline characteristics

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


Treatment related changes carotid wall cbm max

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


Treatment related changes carotid plaque prevalence

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)


Treatment related changes blood pressure and heart rate

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


Safety analysis

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


Key findings from the elsa study

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%


The elsa study summary

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


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