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Cardiovascular Benefits of Blood Pressure and Lipid Lowering: Insights from ASCOT Trial

This study examines the magnitude of cardiovascular benefits from blood pressure and lipid lowering in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). The preliminary data, including 10,305 patients, demonstrates the effectiveness of atorvastatin and amlodipine in reducing the risk of non-fatal myocardial infarction, fatal coronary heart disease, stroke, and other cardiovascular events. The study design, patient inclusion criteria, and key findings are discussed.

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Cardiovascular Benefits of Blood Pressure and Lipid Lowering: Insights from ASCOT Trial

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  1. Magnitude of cardiovascular benefits from blood pressure lowering and lipid lowering Insights from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Peter Sever, Neil Poulter, Bjorn Dahlof, Hans Wedel on behalf of the ASCOT Investigators PRELIMINARY DATA

  2. 10,305 patients TC ≤ 6.5 mmol/L (250 mg/dL) ASCOT-LLA stopped after 3.3 yrs atorvastatin10 mg placebo Double-blind Investigator-led, multinational randomised controlled trial ASCOT: Study design 19,257 hypertensive patients ASCOT-BPLA stopped after 5.5 yrs PROBE design atenolol ± bendroflumethiazide amlodipine ± perindopril

  3. Patient inclusion criteria • Screening and baseline BP • 160/100 mm Hg untreated •  140/90 mm Hg following treatment with 1 or more drugs • Age 40-79 years • No previous MI or current clinical CHD i.e. primary prevention • 3 or more CV risk factors

  4. Systolic and diastolic blood pressure atenolol  thiazide amlodipine  perindopril 180 164.1 SBP 160 163.9 Mean difference 2.7 137.7 140 136.1 mm Hg 120 DBP 94.8 100 Mean difference 1.9 94.5 79.2 80 77.4 60 Last visit Baseline 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 Time (years)

  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. Summary of all end points: BPLA 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) 0.69 (0.63-.077) 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

  7. ASCOT-LLA 2x2 analyses 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 P for interaction = 0.02

  8. 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

  9. ASCOT: BPLA and LLA combined: Insight into optimal CV prevention Rates* / 1000 patient years at end of LLA * Updated figures with late reported events now included

  10. These risk reductions do not take into account the benefits from blood pressure lowering per se

  11. 180 160 140 Systolic Blood Pressure atenolol  thiazide amlodipine  perindopril 164.1 mm Hg 163.9 Mean difference 2.7 137.7 136.1 18 CHD 15 Stroke 12 9 Event Rate* *per 1000 patient years Not randomised to statin 6 3 0 Last visit Baseline 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 Time (years) . Sever P, Poulter N et al. Am J Cardiol. 2005;96 [suppl]:39F-44F

  12. Event rates during the first 6 months of LLA in those not assigned atorvastatin, and rates at the end of LLA in those assigned Amlodipine/Perindopril based treatment and atorvastatin

  13. Estimated benefits of combined blood pressure and lipid loweringfrom meta-analyses of placebo controlled trials

  14. Early in-trial event rates based on small numbers of events. • Early event rates may underestimate rapid onset of benefits from blood pressure and lipid-lowering. • Using Framingham model (validated for CHD estimates in Northern European Populations*) risk reductions from baseline for CHD are greater. * Haq et al. Heart. 1999;81:40-6

  15. Reduction in risk of non-fatal MI and fatal CHD using Framingham model for baseline estimates ** *per 1000 patient years **Variables include SBP, smoking status, total and HDL-cholesterol, presence or absence of LVH, age, gender, presence or absence of diabetes. No correction for on- treatment blood pressure

  16. ASCOT- a multiple risk intervention trial • Identified hypertensive patients most of whom were poorly controlled. • Controlled BP with two intervention strategies. Intervention 1 • Compared beta-blocker/diuretic with calcium blocker/ACEI regimens. Intervention 2 • Investigated benefit of statin in hypertensives with “normal” or modestly raised cholesterol levels. Intervention 3 • Allowed estimate of total benefit from 3 interventions.

  17. Conclusions • Combined benefits from blood pressure reduction, assignment to an amlodipine/perindopril regimen with atorvastatin were substantial. • For CHD events these benefits were greater than predicted and could indicate synergy between atorvastatin and the amlodipine/perindopril regimen. • We estimate treating about 55 patients for one year with an amlodipine – based regimen and atorvastatin compared with former treatment (without a statin ) would prevent one major CHD event.

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