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Presenter Disclosure Information. ASCOT-LLA REVISITED: INTERACTION OF ANTIHYPERTENSIVE AND LIPID-LOWERING THERAPY.

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  1. Presenter Disclosure Information

  2. ASCOT-LLA REVISITED: INTERACTION OF ANTIHYPERTENSIVE AND LIPID-LOWERING THERAPY P Sever (Co-chair), B Dahlöf (Co-chair), N Poulter (Secretary), H Wedel (Statistician), G Beevers, M Caulfield, R Collins, SE Kjeldsen, A Kristinsson, J Mehlsen, G McInnes, M Nieminen, E O’Brien, J Östergren On behalf of the ASCOT Investigators

  3. ASCOT-BPLA and LLA Primary Objectives To compare the effect on non-fatal myocardial infarction (MI) and fatal CHD of : a standard antihypertensive regimen (-blocker +/- diuretic) with a more contemporary regimen (CCB +/- ACE inhibitor) and atorvastatin with placebo in those with total cholesterol < 6.5 mmol/L(250mg/dl)

  4. 10,305 patients TC ≤ 6.5 mmol/L (250 mg/dL) ASCOT-LLA atorvastatin10 mg placebo Double-blind Investigator-led, multinational randomised controlled trial Study design 19,257 hypertensive patients ASCOT-BPLA PROBE design atenolol ± bendroflumethiazide amlodipine ± perindopril

  5. Risk Ratio Primary End Points Nonfatal MI (incl silent) + fatal CHD Secondary End Points Total CV events and procedures Total coronary events Nonfatal MI (excl silent) + fatal CHD All-cause mortality Cardiovascular mortality Fatal and nonfatal stroke Fatal and nonfatal heart failure Tertiary End Points Silent MI Unstable angina Chronic stable angina Peripheral arterial disease Development of diabetes mellitus Development of renal impairment Atorvastatin better Placebo better 0.5 1.0 1.5 Area of squares is proportional to the amount of statistical information ASCOT-LLASummary of all end points Hazard Ratio 0.64 (0.50-0.83) 0.79 (0.69-0.90) 0.71 (0.59-0.86) 0.62 (0.47-0.81) 0.87 (0.71-1.06) 0.90 (0.66-1.23) 0.73 (0.56-0.96) 1.13 (0.73-1.78) 0.82 (0.40-1.66) 0.87 (0.49-1.57) 0.59 (0.38-0.90) 1.02 (0.66-1.57) 1.15 (0.91-1.44) 1.29 (0.76-2.19) Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

  6. 10,305 patients TC ≤ 6.5 mmol/L (250 mg/dL) ASCOT-LLA atorvastatin10 mg placebo Double-blind Study design 19,257 hypertensive patients ASCOT-BPLA PROBE design atenolol ± bendroflumethiazide amlodipine ± perindopril

  7. ASCOT-BPLA :summary of all end points Unadjusted Hazard ratio (95% CI) 0.90 (0.79-1.02) 0.87 (0.76-1.00) 0.87 (0.79-0.96) 0.84 (0.78-0.90) 0.89 (0.81-0.99) 0.76 (0.65-0.90) 0.77 (0.66-0.89) 0.84 (0.66-1.05) 1.27 (0.80-2.00) 0.68 (0.51-0.92) 0.98 (0.81-1.19) 0.65 (0.52-0.81) 1.07 (0.62-1.85) 0.70 (0.63-.078) 0.85 (0.75-0.97) 0.86 (0.77-0.96) 0.84 (0.76-0.92) PrimaryNon-fatal MI (incl silent) + fatal CHD SecondaryNon-fatal MI (exc. Silent) +fatal CHD Total coronary end pointTotal CV event and proceduresAll-cause mortalityCardiovascular mortalityFatal and non-fatal strokeFatal and non-fatal heart failure TertiarySilent MI Unstable anginaChronic stable anginaPeripheral arterial diseaseLife-threatening arrhythmiasNew-onset diabetes mellitusNew-onset renal impairment Post hoc Primary end point + coronary revasc procs CV death + MI + stroke 1.00 1.45 2.00 0.50 0.70 Atenolol  thiazide better Amlodipine  perindopril better The area of the blue square is proportional to the amount of statistical information

  8. Secondary end points Total stroke All coronary events Primary end point minus silent MI Total cardiovascular (CV) events and procedures CV mortality All-cause mortality Heart failure Tertiary end points Development of diabetes Impairment of renal function Pre-specified end points in pre-specified subgroups Life-threatening arrhythmias Other objectives Interaction between statins and antihypertensive treatment on the primary endpoint and total CV events and procedures Health economic analyses Additional objectives include:

  9. ASCOT-LLA Primary endpoint: Non-fatal MI and fatal CHD Atenolol-based treatment Amlodipine-based treatment 4.0 4.0 Atorvastatin Placebo Atorvastatin Placebo 3.0 3.0 16% 53% Cumulative incidence (%) 2.0 2.0 Cumulative incidence (%) 1.0 1.0 HR=0.84 (0.60 - 1.17) p=0.30 HR=0.47 (0.32 - 0.69) p<0.001 0.0 0.0 0.5 0.5 1.0 2.0 1.0 2.0 0.0 2.5 0.0 2.5 1.5 3.0 3.5 1.5 3.0 3.5 Years Years

  10. ASCOT-LLA Primary endpoint: Non-fatal MI and fatal CHD Atenolol-based treatment Amlodipine-based treatment 4.0 4.0 Atorvastatin Placebo Atorvastatin Placebo 3.0 3.0 16% 53% Cumulative incidence (%) 2.0 2.0 Cumulative incidence (%) 1.0 1.0 HR=0.84 (0.60 - 1.17) p=0.30 HR=0.47 (0.32 - 0.69) p<0.001 0.0 0.0 0.5 0.5 1.0 2.0 1.0 2.0 0.0 2.5 0.0 2.5 1.5 3.0 3.5 1.5 3.0 3.5 Years Years

  11. Atenolol-based treatment Amlodipine-based treatment 4.0 4.0 Atorvastatin Placebo Atorvastatin Placebo 3.0 3.0 16% 53% Cumulative incidence (%) 2.0 2.0 Cumulative incidence (%) 1.0 1.0 HR=0.84 (0.60 - 1.17) p=0.30 HR=0.47 (0.32 - 0.69) p<0.001 0.0 0.0 0.5 0.5 1.0 2.0 1.0 2.0 0.0 2.5 0.0 2.5 1.5 3.0 3.5 1.5 3.0 3.5 Years Years

  12. ASCOT-LLA Total cardiovascular events and procedures Amlodipine-based treatment Atenolol-based treatment 12.0 12.0 10.0 15% 10.0 Atorvastatin Placebo Atorvastatin Placebo 27% 8.0 8.0 Cumulative incidence (%) Cumulative incidence (%) 6.0 6.0 4.0 4.0 2.0 2.0 HR=0.73 (0.60 - 0.88) p=0.001 HR=0.85 (0.71 - 1.02) p=0.08 0.0 0.0 0.5 0.5 1.0 2.0 1.0 2.0 2.5 2.5 0.0 1.5 3.0 3.5 0.0 1.5 3.0 3.5 Years Years

  13. ASCOT-LLA Fatal and non-fatal stroke Atenolol-based treatment Amlodipine-based treatment 3.0 3.0 24% Atorvastatin Placebo Atorvastatin Placebo 2.0 2.0 31% Cumulative incidence (%) Cumulative incidence (%) 1.0 1.0 HR=0.76 (0.63 - 1.08) p=0.013 HR=0.69 (0.45 - 1.06) p=0.09 0.0 0.0 0.5 1.0 2.0 2.5 0.0 1.5 3.0 3.5 0.5 1.0 2.0 2.5 0.0 1.5 3.0 3.5 Years Years

  14. Fatal CHD + non-fatal MI n.s. n.s. p<0.0001 p=0.015 Events/1000 patient years Interaction p=0.025

  15. Total CV events and procedures n.s. p=0.08 p=0.001 p=0.021 Events/1000 patient years Interaction p=0.25

  16. Stroke n.s. p=0.06 p=0.09 p=0.04 Events/1000 patient years Interaction p=0.73

  17. On-treatment Fatal CHD + Non-fatal MI Fatal CHD + non-fatal MI Primary + Revascularisation n.s. n.s. n.s. p<0.0001 n.s. n.s. n.s. p=0.003 p<0.0001 p=0.015 p=0.015 p=0.019 Events/1000 patient years Interaction p=0.043 Interaction p=0.025 Interaction p=0.043

  18. CHD events Events ( Rate)* HRAtorvaPlacebo Censoring Time Hazard Ratios (95% CI) 30 days 90 days 180 days 1 Year 2 Years End of Study 0.17(0.02-1.38) 1 (2.4) 6 (14.2) 0.33(0.14-0.78 7 (5.5) 21 (16.6) 0.52(0.30-0.91) 19 (7.5) 36 (14.3) 0.55(0.36-0.84) 34 (6.6) 61 (12.0) 0.62(0.45-0.85) 60 (5.9) 96 (9.5) 0.64(0.50-0.83) 100 (6.0) 154 (9.4) * Per 1000 patient years Placebo better Atorvastatin better

  19. Rates and hazard ratios at various timepoints for non-fatal MI (incl silent) + fatal CHD amongst patients in the Amlodipine arm CHD Event (Rate*) HR (95% CI) Atorvastatin Placebo 0.33 (0.03-3.17) 1 (4.9) 3 (14.8) 0.27 (0.08-0.97) 3 (4.8) 11 (17.7) 0.40 (0.19-0.88) 9 (7.1) 22 (17.7) 0.46 (0.26-0.84) 16 (6.2) 34 (13.5) 0.39 (0.23-0.65) 20 (3.9) 51 (10.2) 0.47 (0.32-0.69) 38 (4.6) 80 (9.8) Hazard Ratios (95% CI) Censoring Time 3.17 30 days 90 days 180 days 1 year 2 years End of study // 0.0 0.5 1.0 1.5 Placebo better Atorvastatin better * Per 1000 patient years

  20. Summary • Benefits of atorvastatin on coronary end points greater in those allocated amlodipine compared with atenolol-based treatment. • A formal test for interaction between lipid-lowering and blood pressure-lowering treatment was of borderline significance for this endpoint. • No significant interaction was evident for two other endpoints (total CV events and procedures and fatal and non-fatal stroke) • Whilst these observations could be a chance finding, there is a plausible biological explanation for a synergistic effect of atorvastatin and amlodipine-based treatment on acute coronary events.

  21. Monocytes LDL Expression of adhesion molecules Vascular endothelium Uptake of LDL Foam cell Monocyte Macrophage Oxidised LDL Smooth muscle cells

  22. SMC dedifferentiation To synthetic phenotype Macrophage Foam cells Cytokine release SMC migration and proliferation

  23. Formation of fibrous cap

  24. Apoptosis MMPs Lipid-laden macrophage Destruction of inter-cellular matrix

  25. Plaque rupture

  26. Ca2+ CCB Loss of Functionality of L-type VOC • CCBs ineffective SMC DEDIFFERENTIATION Contractile phenotype Synthetic phenotype Presence of statins leads to growth arrest and re-expressionof functioningL-type VOCs L-type VOC • CCBs effective

  27. An additional mechanism?

  28. SMC: reversion to a more differentiated phenotype

  29. Hypothesis • Electrochemical bonding of atorvastatin and amlodipine in the lipid bilayer of vascular smooth muscle cell membranes (Mason) • Restoration of functionality of L-type calcium channels in vsm cells which is lost during migration and proliferation( de-differentiation) due to an action of atorvastatin inducing growth arrest of cells ,and restoration of responsiveness of vsm to CCBs • Return of vsm cells to more differentiated phenotype • Stabilisation of plaque possibly due to reduced destruction and apoptosis of vsm cells, a reduction in release of MMPs and preservation of intercellular matrix.

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