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ELSA The European Lacidipine Study on Atherosclerosis Principal Results

ELSA The European Lacidipine Study on Atherosclerosis Principal Results. Relationship of hypertension and atherosclerosis. Hypertension. Increased turbulent flow (particularly at bifurcation points). Mechanical stress of high blood pressure. Endothelial damage. Increased risk

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ELSA The European Lacidipine Study on Atherosclerosis Principal Results

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  1. ELSAThe European Lacidipine Study on AtherosclerosisPrincipal Results

  2. Relationship of hypertension and atherosclerosis Hypertension Increased turbulent flow (particularly at bifurcation points) Mechanical stress of high blood pressure Endothelial damage Increased risk of atherosclerotic lesions Release of vasoconstrictive factors (endothelin) Increased permeability for lipids and free radicals Zanchetti, 1992

  3. The atherosclerotic process Monocytes Oxygen free radicals Circulating monocytes Endothelium Native LDL Native LDL Endothelial injury SMC Endothelial cells Macrophages Smooth muscle cell (SMC) - Resident monocyte/ macrophage Foam cells Oxygen free radicals Macrophages Free radicals Oxidatively modified LDL Oxidatively modified LDL Foam cell OxidisedLDL Soma et al., 1994

  4. Lacidipine: Dual action against atherosclerotic processes Macrophage activation/ foam cell formation Oxidation of LDL cholesterol Calcium antagonist Antioxidant Vascular smooth muscle cell migration Thrombocyte aggregation Gaviraghi et al., 1998

  5. 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

  6. Antiatherosclerotic properties of lacidipine: Pre-clinical data (2) • 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 1Krenek et al., 2001; 2Cominacini et al., 1999; 3Cristofori et al., 2000

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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                   ELSA1        MIDAS2     VHAS1       PREVENT3 0 500 1000 1500 2000 2500 Number of patients 1Zanchetti et al., 1998; 2Borhani et al., 1996; 3Mancini et al., 2000

  13. 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)

  14. Patient populations • Safety, N = 2,334 All patients randomised and receiving at least one dose of DB treatment • Intention to treat (ITT), N = 2,035 Patients from the safety population having at least one baseline and one subsequent readable scan • Per-Protocol 1 (PP1), N = 1,884 Patients from the ITT population with no major protocol violations • Per-Protocol 2 (PP2), N = 1,807 Patients from the ITT population with no major protocol violations and with at least one scan after baseline taken under active treatment • Completers, N = 1,519 All PP patients having completed the 4-year DB treatment period

  15. 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

  16. CBMmax progression – repeated measurements model ITT PP1 Completers PP2 Patient number: Atenolol 1006 926 764 901 Lacidipine 1022 942 765 906 Estimated treatment effect (mm): Lacidipine vs. atenolol -0.0227 -0.0276 -0.0281 -0.0293 -0.0330 -0.0381 -0.0394 -0.0399 95% Confidence interval -0.0124 -0.0171 -0.0167 -0.0187 Statistics (P) < 0.0001 < 0.0001 < 0.0001 < 0.0001

  17. 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

  18. Treatment-related changes: Common carotid and carotid bifurcation IMT Mmax changes in common carotid (CC) and carotid bifurcation (CB) with lacidipine compared with atenolol (repeated measurements model) P-values Treatment Time Baseline Mmax CC < 0.0001 < 0.0001 < 0.0001 ITT CB = 0.0085 < 0.0001 < 0.0001 CC < 0.0001 < 0.0001 < 0.0001 PP1 CB = 0.0015 < 0.0001 < 0.0001 CC < 0.0001 < 0.0001 < 0.0001 PP2 CB = 0.0004 < 0.0001 < 0.0001 CC < 0.0001 < 0.0001 < 0.0001 Completers CB = 0.0013 < 0.0001 < 0.0001 -0.05 -0.04 -0.03 -0.02 -0.01 0 +0.01 Lacidipine better Atenolol better Estimated lacidipine effect (mm)

  19. 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)

  20. 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

  21. 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

  22. 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

  23. 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

  24. 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%

  25. 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

  26. Clinical significance of the ELSA results • 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 1Hodis et al., 1998; 2Salonen & Salonen, 1993; 3Bots et al., 1997; 4Chambless et al., 2000

  27. 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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