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A randomised controlled trial of the prevention of CHD and other vascular events by BP and cholesterol lowering in a factorial study design B.Dahlof (Co-chair),

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Presentation on theme: "A randomised controlled trial of the prevention of CHD and other vascular events by BP and cholesterol lowering in a factorial study design B.Dahlof (Co-chair),"— Presentation transcript:

1 A randomised controlled trial of the prevention of CHD and other vascular events by BP and cholesterol lowering in a factorial study design B.Dahlof (Co-chair), P.Sever (Co-chair), N. Poulter (Secretary) H. Wedel (Statistician), G. Beevers, M. Caulfield, R. Collins S. Kjeldsen, A. Kristinsson, J. Mehlsen, G. McInnes, M. Nieminen E. O’Brien, J. Östergren, on behalf of the ASCOT Investigators

2 ASCOT- BPLA: Rationale
Insufficient outcome data on newer types of BP-lowering agents, especially in specific combination treatment regimens Less-than-expected CHD prevention using standard therapy

3 ASCOT- BPLA Primary Objective
To compare the effect on non-fatal myocardial infarction (MI) and fatal CHD of the standard antihypertensive regimen (-blocker ± diuretic) with a more contemporary regimen (CCB ± ACE inhibitor)

4 Additional objectives include:
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 Health economic analyses

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

6 Treatment algorithm to BP targets < 140/90 mm Hg
or < 130/80 mm Hg in patients with diabetes amlodipine 5-10 mg atenolol mg add add bendroflumethiazide-K mg perindopril 4-8 mg add doxazosin GITS 4-8 mg add additional drugs, eg, moxonidine/spironolactone 3

7 Patient inclusion criteria
Screening and baseline BP  160/100 mm Hg untreated  140/90 mm Hg following treatment with 1 or more drugs Age years No previous MI or current clinical CHD 3 or more CV risk factors 2

8 Study power and recruitment (Feb 1998-May 2000)
1567 2382 2226 3984 9098 POWER: PRIMARY END POINT Relative additional benefit (ITT) % Significance level 5% Power % Estimated sample size 18,000 Persons with events Recruitment into ASCOT started in February 1998 and continued through May Most patients were recruited from family practice. In the Nordic countries, 686 family practices randomized patients, and in the UK and Ireland patients were recruited by 32 regional centres to which patients were referred by their family physicians. TOTAL RECRUITED 19,257

9 Baseline characteristics
amlodipine  perindopril atenolol  thiazide Demographics and clinical characteristics n = n = 9618 Woman (23.4%) (23.5%) White (95.3%) (95.3%) Current smoker (32.9%) (32.3%) Age (years) (8.5) (8.5) SBP (mm Hg) (18.1) (18.0) DBP (mm Hg) (10.4) (10.4) Heart rate (bpm) (12.7) (12.6) BMI (kg/m2) (4.6) (4.5) Drug therapy Previous antihypertensive treatments (19.1%) (19.0%) (44.4%) (44.5%) ≥ (36.5%) (36.5%) Lipid-lowering therapy (10.9%) (10.4%) Aspirin (19.2%) (19.1%) Values are number of patients, (%) or mean (SD)

10 Data safety monitoring board (DSMB)
In October 2004 the DSMB recommended that the BP arm of ASCOT should be stopped on account of concerns that those patients receiving atenolol  thiazide would continue to be disadvantaged compared with the comparator group The Steering Committee endorsed the recommendation of the DSMB, and trial closure began Dec, 2004 and ended June 2005. In September 2002, the Data Safety Monitoring Board (DSMB) recommended that the double-blind cholesterol-lowering study arm be terminated on the grounds that atorvastatin demonstrated a highly significant reduction in the primary end point as well as a significant reduction in the secondary end point of stroke. The Steering Committee endorsed the recommendation of the DSMB, and the lipid arm was closed after a median follow-up period of 3.3 years.

11 Statistical methods Based on an intention-to-treat analysis
Time to first primary event Log-rank procedure and Cox’s Proportional Hazards were used to calculate confidence intervals Cumulative incidence curves were generated using the Kaplan-Meier method The time to first primary endpoint event in the atorvastatin and placebo groups was compared on an intention-to-treat basis. All analyses excluded end points deemed invalid by the end point committee, with statistical censoring enforced at the end of the study on Oct. 1, 2002, or death before that date. The main analyses used the log-rank procedure and the Cox’s proportional hazards model to calculate CI. Cumulative incidence curves were generated by the Kaplan-Meier method for all major endpoints in the active and placebo groups. . Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

12 ASCOT patient population risk factor profile
All patients in ASCOT have hypertension plus ≥ 3 risk factors for CHD Hypertension Age ≥ 55 years Male Microalbuminuria/proteinuria Smoker Family history of CHD Plasma TC:HDL-C ≥ 6 Type 2 diabetes Certain ECG abnormalities LVH Previous cerebrovascular events Peripheral vascular disease 100 84 77 61 30 27 24 24 14 13 11 6 10 20 30 40 50 60 70 80 90 100 Patients with risk factor (%)

13 trial design 19,342 randomised to antihypertensive therapy
85 excluded before end of study due to irregularities 19,257 randomised 9,639 assigned and received amlodipine  perindopril 9,618 assigned and received atenolol  thiazide 121 with incomplete information 81 alive at last visit 24 withdrawn consent 16 lost to follow-up 171 with incomplete information 102 alive at last visit 36 withdrawn consent 33 lost to follow-up 9639 assessed for primary endpoint on intention-to-treat basis 9,518 with complete information (8,780 alive 738 dead) 9618 assessed for primary endpoint on an intention-to-treat basis 9,447 with complete information ( 8,627 alive 820 dead)

14 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 100 94.8 Mean difference 1.9 94.5 79.2 80 77.4 60 Baseline 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 Last visit Time (years)

15 Mean proportion of time on antihypertensive medication by treatment group
Year 1 All Study Randomised to Amlodipine Amlodipine 88.2 82.5 Perindopril 46.2 58.5 Amlodipine + perindopril 39.1 49.5 Randomised to atenolol Atenolol 87.4 79.4 Bendroflumethiazide 56.6 65.7 Atenolol + bendroflumethiazide 49.1 54.9

16 Primary end point: Non-fatal MI, fatal CHD
% 5.0 Atenolol  thiazide (No. of events =474) 4.0 Amlodipine  perindopril (No. of events = 429) 3.0 2.0 HR = 0.90 (0.79­1.02) p = 1.0 0.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide 0.0 1.0 2.0 3.0 4.0 5.0

17 Endpoints: Non-fatal MI (excl silent) + fatal CHD
% 5.0 4.0 Atenolol  thiazide (No. of events 444) 3.0 Amlodipine  perindopril (No. of events 390) 2.0 HR = 0.87 (0.76­1.00) p = 1.0 0.0 Years 0.0 1.0 2.0 3.0 4.0 5.0 Number at risk Amlodipine  perindopril Atenolol  thiazide

18 Amlodipine  perindopril
Primary end point + coronary revascularisation procedures % 8.0 7.0 Atenolol  thiazide (No. of events 688) 6.0 5.0 Amlodipine  perindopril (No. of events 596) 4.0 3.0 2.0 HR = 0.86 (0.77­0.96) p = 1.0 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

19 Total coronary end point
% 10.0 Atenolol  thiazide (No. of events 852) 8.0 6.0 Amlodipine  perindopril (No. of events 753) 4.0 2.0 HR = 0.87 (0.79­0.96) p = 0.0 0.0 1.0 2.0 3.0 4.0 Years 5.0 Number at risk Amlodipine  perindopril Atenolol  thiazide

20 Fatal and non-fatal stroke
% 5.0 Atenolol  thiazide (No. of events 422) 4.0 3.0 Amlodipine  perindopril (No. of events 327) 2.0 HR = 0.77 (0.66­0.89) p = 1.0 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

21 Total CV events and procedures
% 18.0 Atenolol  thiazide (No. of events 1602) 16.0 14.0 12.0 Amlodipine  perindopril (No. of events 1362) 10.0 8.0 6.0 4.0 HR = 0.84 (0.78­0.90) p < 2.0 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

22 Amlodipine  perindopril
CV mortality % 3.5 Atenolol  thiazide (No. of events 342) 3.0 2.5 2.0 Amlodipine  perindopril (No. of events 263) 1.5 1.0 HR = 0.76 (0.65­0.90) p = 0.5 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

23 Amlodipine  perindopril
All-cause mortality % 10.0 8.0 Atenolol  thiazide (No. of events 820) 6.0 Amlodipine  perindopril (No. of events 738) 4.0 2.0 HR = 0.89 (0.81­0.99) p = 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

24 Fatal and non-fatal heart failure
% 1.8 1.6 Atenolol  thiazide (No. of events 159) 1.4 1.2 Amlodipine perindopril (No. of events 134) 1.0 0.8 0.6 0.4 HR = 0.84 (0.66­1.05) p = 0.2 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

25 Amlodipine  perindopril
Unstable angina % 1.2 Atenolol  thiazide (No. of events 106) 1.0 0.8 Amlodipine  perindopril (No. of events 73) 0.6 0.4 HR = 0.68 (0.51­0.92) p = 0.2 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

26 Amlodipine  perindopril
Chronic stable angina % 2.5 Atenolol  thiazide (No. of events = 208) 2.0 1.5 Amlodipine  perindopril (No. of events = 205) 1.0 0.5 HR = 0.98 (0.81­1.19) p = 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

27 Peripheral arterial disease
% 2.5 2.0 Atenolol  thiazide (No. of events = 202) 1.5 1.0 Amlodipine  perindopril (No. of events = 133) 0.5 HR = 0.65 (0.52­0.81) p = 0.0 Years 0.0 1.0 2.0 3.0 4.0 5.0 Number at risk Amlodipine  perindopril Atenolol  thiazide

28 Life-threatening arrhythmias
% 0.3 Atenolol  thiazide (No. of events = 25) 0.2 Amlodipine  perindopril (No. of events = 27) 0.1 HR = 1.07 (0.62 ­1.85) p = 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

29 New-onset renal impairment
% 5.0 Atenolol  thiazide (No. of events = 469) 4.0 Amlodipine  perindopril (No. of events = 403) 3.0 2.0 HR = 0.85 (0.75­0.97) p = 1.0 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

30 New-onset diabetes mellitus
% 10.0 Atenolol  thiazide (No. of events = 799) 8.0 6.0 Amlodipine  perindopril (No. of events = 567) 4.0 2.0 HR = 0.70 (0.63­0.78) p < 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

31 Amlodipine  perindopril
CV death + MI + stroke % 10.0 Atenolol  thiazide (No. of events = 937) 8.0 6.0 Amlodipine  perindopril (No. of events = 796) 4.0 2.0 HR = (0.76­0.92) p < 0.0 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

32 Summary of all end points
Unadjusted Hazard ratio (95% CI) 0.90 ( ) 0.87 ( ) 0.87 ( ) 0.84 ( ) 0.89 ( ) 0.76 ( ) 0.77 ( ) 0.84 ( ) 1.27 ( ) 0.68 ( ) 0.98 ( ) 0.65 ( ) 1.07 ( ) 0.70 ( ) 0.85 ( ) 0.86 ( ) 0.84 ( ) Primary Non-fatal MI (incl silent) + fatal CHD Secondary Non-fatal MI (exc. Silent) +fatal CHD Total coronary end point Total CV event and procedures All-cause mortality Cardiovascular mortality Fatal and non-fatal stroke Fatal and non-fatal heart failure Tertiary Silent MI Unstable angina Chronic stable angina Peripheral arterial disease Life-threatening arrhythmias New-onset diabetes mellitus New-onset renal impairment Post hoc Primary end point + coronary revasc procs CV death + MI + stroke 0.50 0.70 1.00 1.45 2.00 Amlodipine  perindopril better Atenolol  thiazide better The area of the blue square is proportional to the amount of statistical information

33 Total CV events and procedures among subgroups
Diabetes No diabetes Current smoker Non-current smoker Obese Non-obese Older (>60 years) Younger (≤60 years) Female Male LVH according to ECG or ECHO No LVH according to ECG or ECHO Previous vascular disease No previous vascular disease Renal dysfunction No renal dysfunction With metabolic syndrome Without metabolic syndrome All patients 0.60 0.70 0.80 0.90 1.00 1.50 Amlodipine  perindopril better Atenolol  thiazide better The area of the black square is proportional to the amount of statistical information

34 Total CV events and procedures among subgroups
p value <0.0001 <0.0001 < <0.0001 < <0.0001 Heterogeneity p 0.5205 0.1138 0.6753 0.7816 0.2889 0.6364 0.4863 0.7130 0.9417 Diabetes No diabetes Current smoker Non-current smoker Obese Non-obese Older (>60 years) Younger (≤60 years) Female Male LVH according to ECG or ECHO No LVH according to ECG or ECHO Previous vascular disease No previous vascular disease Renal dysfunction No renal dysfunction With metabolic syndrome Without metabolic syndrome All patients 0.60 0.70 0.80 0.90 1.00 1.50 Amlodipine  perindopril better Atenolol  thiazide better The area of the black square is proportional to the amount of statistical information

35 Adverse events leading to treatment discontinuation
Amlodipine  perindopril (%) Atenolol  thiazide (%) Total (24.5) (25.0) Serious (1.7) (2.6)* * p<0.0001

36 Amlodipine  perindopril Atenolol  thiazide n (%)
Adverse events Adverse event* Amlodipine  perindopril n (%) Atenolol  thiazide n (%) p-value Bradycardia 34 (0.4) 536 (6) <0.0001 Chest pain 740 (8) 849 (9) 0.0040 Cough 1859 (19) 782 (8) Diarrhoea 377 (4) 548 (6) Dizziness 1183 (12) 1555 (16) Dyspnoea 599 (6) 987 (10) Eczema 493 (5) 383 (4) 0.0002 Erectile dysfunction 556 (6) 707 (7) Fatigue 1556 (16) Joint swelling 1371 (14) 308 (3) Lethargy 202 (2) 525 (6) Oedema peripheral 2188 (23) 588 (6) Peripheral coldness 81 (1) 579 (6) Vertigo 642 (7) 745 (8) 0.0039 * Adverse events with incidence >5% and difference of more than 1%

37 ASCOT Committees Executive and Writing Committee
B Dahlöf, Co-Chairman, Gothenburg, P Sever, Co-Chairman, London, N Poulter, Secretary, London, H Wedel, Statistician, Gothenburg. Steering Committee A Adderkin, London, DG Beevers, Birmingham, J Buch, New York (non-voting), M Caulfield, London, R Collins, Oxford, B Dahlöf, Gothenburg, A Jarl, Stockholm (non-voting), SE Kjeldsen, Oslo, A Kristinsson, Reykjavik, J Mehlsen, Copenhagen, G McInnes, Glasgow, M Nieminen, Helsinki, N Poulter, London, E O'Brien, Dublin, P Sever, London, H Wedel, Gothenburg, J Östergren, Stockholm, Servier representative, Paris (non-voting). Working Group A Adderkin, London, J Buch, New York, S Cavanaugh (up to 2003), New York, R Chamberlain, New York, B Dahlöf, Gothenburg, S Gee, London, A Holmner, Gothenburg, A Jarl, Stockholm, N Poulter, London, P Sever, London, H Wedel, Gothenburg. Data Safety Monitoring Board J Cohn, Minneapolis, L Erhardt, Malmö, K Fox, London, A Oden, Gothenburg, S Pocock, London, J Tuomilehto, Helsinki. Endpoint Committee U Dahlström, Linköping, F Fyhrquist, Helsinki, H Hemingway, London, K Midtbo, Oslo. Substudy Committee M Caulfield, London, B Dahlöf, Gothenburg, T Kahan, Stockholm, J Mehlsen, Copenhagen, M Nieminen, Helsinki, E O'Brien, Dublin, I Os, Oslo, N Poulter, London, P Sever, London, S Thom, London.

38 Possible explanations for the observed differences in outcomes
Better BP lowering with amlodipine  perindopril Non-BP-lowering benefits of amlodipine  perindopril Non-BP-related disadvantages of atenolol  thiazide Adverse interaction between atenolol  thiazide and statin Beneficial interaction between amlodipine  perindopril and statin

39 Variables which differed significantly (baseline - final visit) between treatment regimens
Mean differences (Amlodipine  perindopril - Atenolol  thiazide) Changes baseline to final visit p-value Systolic BP (mm Hg) -1.78 <0.0001 Diastolic BP (mm Hg) -2.05 Heart rate (bpm) 11.12 Weight (kg) -0.79 HDL-cholesterol (mmol/L) 0.11 Triglycerides (mmol/L) -0.23 Glucose (mmol/L) -0.20 Creatinine (µmol/L) -5.06 Potassium (mmol/L) 0.05

40 Endpoints evaluated Primary endpoint + coronary revascularisation (coronary events) Non-fatal and fatal stroke Rationale Significantly different rates Potentially different mechanisms Sufficient power

41 The role of BP differences?
Methods Temporal association Serial mean matching Updated Cox regression adjustment Which BP measure? SBP DBP MBP - [(SBP + DBP) / 2] Pulse pressure When? Latest One year recurrent average Accumulated mean

42 Differences in coronary event rates and in BP over time
Time interval Accumulated differences (mmHg) Atenolol  thiazide - Amlodipine  perindopril SBP DBP 0-6 months 4.95 1.72 year 4.03 1.99 1 - 2 years 2.62 1.89 2 - 3 years 2.02 1.76 3 - 4 years 1.85 1.88 4 - 5 years 1.62 > 5 years 1.55 1.78 All study 2.76 1.91 0.50 0.25 0.70 1.00 1.45 2.00 2.85 Hazard ratio Amlodipine  perindopril better Atenolol  thiazide better Time interval Accumulated differences (mmHg) Atenolol  thiazide - Amlodipine  perindopril SBP DBP 0-6 months 4.95 1.72 0 - 1 year 4.51 1.86 0 - 2 years 3.67 1.89 0 - 3 years 3.24 1.87 0 - 4 years 3.01 0 - 5 years 2.85 1.91 All study 2.76 0.50 0.25 0.70 1.00 1.45 2.00 2.85 Amlodipine  perindopril better Atenolol  thiazide better Hazard ratio

43 Differences in stroke event rates and in BP over time
Time interval Accumulated differences (mmHg) Atenolol  thiazide - Amlodipine  perindopril SBP DBP 0-6 months 4.95 1.72 year 4.03 1.99 1 - 2 years 2.62 1.89 2 - 3 years 2.02 1.76 3 - 4 years 1.85 1.88 4 - 5 years 1.62 > 5 years 1.55 1.77 All study 2.76 1.91 0.50 0.25 0.70 1.00 1.45 2.00 2.85 Hazard ratio Amlodipine  perindopril better Atenolol  thiazide better Time interval Accumulated differences (mmHg) Atenolol  thiazide - Amlodipine  perindopril SBP DBP 0-6 months 4.95 1.72 0 - 1 year 4.51 1.86 0 - 2 years 3.67 1.89 0 - 3 years 3.24 1.87 0 - 4 years 3.01 0 - 5 years 2.85 1.91 All study 2.76 0.50 0.25 0.70 1.00 1.45 2.00 2.85 Amlodipine  perindopril better Atenolol  thiazide better Hazard ratio

44 Serial mean matching: Methods
Take Amlodipine ± perindopril cohort at each of five time points plus baseline % Select “atenolol ± thiazide” person closest to mean after randomisation Mean Amlodipine ± perindopril (all patients) Atenolol ± thiazide matched subset NB: n> 7500 (86%) SBP Add others sequentially to maintain group SBP matching Maximum mean SBP group difference = 0.02 mm Hg 9% of coronary events and 14% of stroke events excluded Multiple Cox regression - adjusted HR in 6 periods Further adjustment for age and number of risk factors

45 Serial mean matching: Results
Hazard ratio unadjusted Pooled hazard ratio SMM adjusted p-value for adjusted HR Primary endpoint + Coronary revascularisation 0.86 ( ) 0.87 ( ) 0.0177 Fatal and non-fatal stroke 0.77 ( ) 0.83 ( ) 0.0147

46 Hazard ratios for treatment effect on coronary events adjusted for accumulated mean levels of variables that differed Coronary events HR p-value Unadjusted 0.86 0.0058 Systolic BP 0.88 0.0258 Diastolic BP 0.0065 Mean BP* 0.0205 Pulse pressure 0.87 0.0170 Heart rate 0.85 0.0201 Glucose 0.0041 HDL cholesterol 0.90 0.0610 Triglycerides 0.0043 Creatinine 0.0091 Potassium 0.0045 Weight 0.0053 * Mean BP = (SBP/DBP)/2

47 Fatal and non-fatal stroke
Hazard ratios for treatment effect on stroke events adjusted for accumulated mean levels of variables that differed Fatal and non-fatal stroke HR p-value Unadjusted 0.77 0.0003 Systolic BP 0.83 0.0144 Diastolic BP 0.80 0.0033 Mean BP* 0.84 0.0170 Pulse pressure 0.0026 Heart rate 0.74 0.0007 Glucose 0.78 HDL cholesterol 0.76 0.0002 Triglycerides 0.0008 Creatinine 0.79 0.0014 Potassium Weight * Mean BP = (SBP/DBP)/2

48 Amlodipine  perindopril better Atenolol  thiazide better
Impact on the treatment effect on coronary events after adjustment for BP and all variables that differed Hazard ratio 95% CI Unadjusted 0.86 SBP 0.88 SBP + covariates 0.93 SBP + DBP + covariates 0.92 MBP** + covariates 0.94 PP + covariates 0.91 Hazard ratio 95% CI Unadjusted 0.86 SBP 0.88 SBP + covariates 0.93 SBP + DBP + covariates 0.92 MBP** + covariates 0.94 PP + covariates 0.91 Hazard ratio 95% CI Unadjusted 0.86 SBP 0.88 SBP + covariates 0.93 SBP + DBP + covariates 0.92 MBP** + covariates 0.94 PP + covariates 0.91 Amlodipine  perindopril better Atenolol  thiazide better p-value 0.0058 0.0258 0.3276 0.2744 0.3519 0.1791 0.50 0.70 1.00 1.45 Hazard ratio ** MBP = (SBP+DBP)/2

49 Amlodipine  perindopril better Atenolol  thiazide better
Impact on the treatment effect on stroke events after adjustment for BP and all variables that differed Hazard ratio 95% CI Unadjusted 0.77 Mean BP 0.84 SBP + covariates 0.85 SBP + DBP + covariates 0.87 MBP** + covariates PP + covariates 0.80 Hazard ratio 95% CI Unadjusted 0.77 Mean BP 0.84 SBP + covariates 0.85 SBP + DBP + covariates 0.87 MBP** + covariates PP + covariates 0.80 Hazard ratio 95% CI Unadjusted 0.77 Mean BP 0.84 SBP + covariates 0.85 SBP + DBP + covariates 0.87 MBP** + covariates PP + covariates 0.80 Amlodipine  perindopril better Atenolol  thiazide better p-value 0.0003 0.0170 0.0836 0.1386 0.1380 0.0164 0.50 0.70 1.00 1.45 Hazard ratio ** MBP = (SBP+DBP)/2

50 Summary Several potentially important variables including BP differed post-randomisation between 2 treatment groups No temporal association between BP differences and event rate differences SMM for SBP and updated Cox regression analyses suggested BP accounted for about 15% of coronary differences and 30% of stroke differences Full multivariate adjustment accounted for about 50% of coronary differences (mainly HDL-C differences) and 40% of strokes Residual differences are large for stroke but non-significant for coronary and stroke events

51 Conclusions These analyses are compatible with the possibility that CV event differences were explained by the variables considered BP differences unlikely single explanation Residual differences, albeit non-significant, are large especially for stroke ASCOT provides implications for optimal CV prevention independent of these analyses

52 ASCOT: BPLA and LLA combined: Insight into optimal CV prevention (2)
Rates / 1000 patient years Endpoint Amlodipine  perindopril + statin Atenolol  thiazide + placebo Relative risk reduction Fatal MI and non-fatal CHD 4.8 9.2 48% Fatal and non-fatal stroke 4.6 8.2 44%

53 Final conclusions Amlodipine  perindopril based therapy confers an advantage over atenolol  thiazide based therapy on all major CV end points, all-cause mortality and new-onset diabetes Irrespective of the reasons for benefit, the standard regimen of beta-blocker  thiazide should not be preferred to the amlodipine  perindopril regimen for most patients Compared with standard antihypertensive therapy without statin therapy, the amlodipine  perindopril regimen plus atorvastatin reduced coronary and stroke events by almost 50%

54 AHA 2006 Results CAFE study, a substudy of ASCOT

55 Central vs brachial bloodpressure
Are antihypertensive drugs equal in lowering central bloodpressure? What determines central bloodpressure ? What are the consequences of lower central bloodpressure?

56 CAFE study: Rationale Brachial blood pressure is a strong predictor of clinical outcomes in people with hypertension It is assumed that brachial blood pressure accurately reflects pressures in the central aorta and thus left ventricular load This assumption may not be valid in all circumstances because different classes of blood pressure-lowering drugs may differentially influence central aortic blood pressures In clinical trials comparing different blood pressure lowering-drugs, clinical outcomes could be influenced by drug effects on central aortic pressures, despite similar effects on brachial blood pressure Dr Williams was the principal investigator of The CAFÉ substudy of ASCOT CAFE studied effects of two antihypertensive regimens on the relationship between central and peripheral arterial blood pressure. In other words, is it enough to assess blood pressure efficacy of antihypertensive drugs at the level of brachial artery, as doctors do in their every day practice. The secondary objective was to define whether treated central arterial blood pressure is a better predictor of outcome, when compared to treated conventional blood pressure measurements. Knowing that Coversyl has extensive file proving its beneficial effects on structure and function of large arteries in both monotherapy and combination, one could expect positive results.

57 CAFE : Background (1) In clinical trials comparing different blood pressure lowering-drugs, clinical outcomes could be influenced by drug effects on central aortic pressures, despite similar effects on brachial blood pressure This hypothesis required testing in a prospective clinical outcomes trial evaluating 2 different blood pressure-lowering treatment regimens

58 CAFE : Background (2) The Conduit Artery Functional Evaluation (CAFE) study was designed to test this hypothesis as a major substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

59 CAFE Hypothesis Primary Objective
The different blood pressure-lowering regimens in ASCOT (atenolol ± thiazide versus amlodipine ± perindopril) would produce different effects on central aortic pressures and hemodynamics despite similar effects on brachial blood pressure Secondary Objective Central aortic pressures would be an important determinant of clinical outcomes in ASCOT Williams B. et al. J Hum Hypertens. 2001; 15 (suppl 1): S69-S73

60 Methods Seated brachial blood pressure measured using Omron 705CP
Pulse wave analysis 10 second sampling of radial artery pulse waves were recorded by tonometry The radial pulse wave was calibrated to brachial blood pressure and transformed to derive a central aortic pressure wave using the Sphygmocor© apparatus (v7)

61 CAFE study Profile 2199 subjects recruited from 5 UK ASCOT centers
126 excluded due to heart rate irregularity/poor waveforms 2073 evaluable for tonometry 1042 received Amlodipine-based regimen 1031 received atenolol-based regime 4 subjects incomplete information, 1 alive at last visit, 2 withdrawn consent, 1 lost to follow-up 1 subject incomplete information, withdrawn consent 1031 assessed on an intention-to-treat basis 1030 complete information (989 alive, 41 dead) 1042 assessed on an intention-to-treat basis 1038 complete information (997 alive, 41 dead)

62 Baseline Demographics (1)
CAFE ASCOT Atenolol-based n=1031 Amlodipine-based n=1042 n=9639 n=9618 Women 189 (18.3%) 208 (20%) 2257 (23.5%) 2258 (23.4%) Age (years) 62.6 (8.3) 62.9 (8.2) 63.0 (8.5) White 886 (85.9%) 892 (85.6%) 9170 (95.3%) 9187 (95.3%) Current smoker 251 (24.3%) 267 (25.6%) 3109 (32.3%) 3168 (32.9%) SBP mm Hg 159.9 (16.6) 161 (18.4) 163.9 (18) 164.1 (18.1) DBP (mm Hg) 92.4 (9.6) 92.6 (9.8) 94.5 (10.4) 94.8 (10.4) Heart rate (bpm) 71.8 (12.3) 71.2 (12.4) 71.8 (12.6) 71.9 (12.7) BMI (kg/m2) 29 (4.5) 29.1 (4.7) 28.7 (4.5) 28.7 (4.6) Height (cm) 170.7 (8.7) 170.2 (9.4) NA Total cholesterol (mg/dL) 224.3 (38.7) 224.3 (42.5) 228.2 (42.5) LDL-cholesterol (mg/dL) 143.1 (34.8) 146.9 (38.7) HDL-cholesterol (mg/dL) 50.3 (15.5) Triglycerides (mg/dL) 159.4 (88.6) 159.4 (8.6) 168.3 (88.6) Glucose (mg/dL) 110 (38) 112 (38) Creatinine (mg/dL) 1.08 (0.18) 1.09 (0.19) 1.09 (0.18)

63 Baseline Demographics (2)
CAFE ASCOT Atenolol-based n=1031 Amlodipine-based n=1042 n=9639 n=9618 Medical history Prior stroke/TIA 76 (7.4%) 62.9 (8.2) 63.0 (8.5) Diabetes 252 (24.4%) 892 (85.6%) 9170 (95.3%) 9187 (95.3%) LVH (echo or ECG) 237 (23%) 267 (25.6%) 3109 (32.3%) 3168 (32.9%) Peripheral vascular disease 61 (5.9%) 59 (5.7%) 613 (6.4%) 586 (6.1%) Other relevant CV disease 22 (2.1%) 27 (2.6%) 486 (5.1%) 533 (5.5) Mean (SD) # risk factors 3.7 (0.9) Drug therapy BP treatment naive 109 (10.6%) 100 (9.6%) 1825 (19%) 1841 (19.1%) Lipid-lowering therapy 120 (11.6%) 120 (11.5%) 1004 (10.4%) 1046 (10.9%) Aspirin use 244 (23.7%) 274 (26.3%) 1837 (19.1%) 1851 (19.2%)

64 Mean Proportion of Time (%) on BP Lowering Medication by Treatment Group*
Year 1 All study Randomized to Amlodipine Amlodipine 90.0 80.7 Perindopril 56.0 66.7 Amlodipine + perindopril 47.8 55.5 Randomized to Atenolol Atenolol 88.1 73.5 Bendroflumethiazide 69.8 74.2 Atenolol + bendroflumethiazide 60.2 59.6 * From time of randomization into ASCOT

65 CAFE Study: Different waveforms demonstrate lower central BP in CCB/ACEI arm
amlodipine ± perindopril atenolol ± bendroflumethiazide Peripheral waveform Central aortic waveform Williams B. Circulation 2006.

66 BP lowering drugs have different effects on central bloodpressure
Central aortic SBP difference: 4.3 mm Hg (P < ) Central aortic PP difference: 3.0 mm Hg (P < ) Williams B. Circulation 2006.

67 Results summary (1) Atenolol±thiazide was associated with higher central aortic systolic pressure and higher central aortic pulse pressure, despite similar brachial pressures, when compared with amlodipine±perindopril Central aortic outgoing pressure wave (P1 height) was lower with atenolol±thiazide vs amlodipine±perindopril Pulse wave augmentation and the percentage of the central aortic pressure wave attributable to wave reflection was increased by atenolol±thiazide compared with amlodipine±perindopril

68 Central vs brachial bloodpressure
Are antihypertensive drugs equal in lowering central bloodpressure? What determines central bloodpressure ? What are the consequences of lower central bloodpressure?

69 Pressure Wave Reflection at the Heart What is it?
If there was no wave reflection (ie. the aorta was an open-ended tube providing a simple resistance to flow), then: the pressure wave in the aortic root would be the same as the flow wave (see graph). Figure 1 Figure 1 Menu

70 Pressure Wave Reflection at the Heart What is it?
Now if we connect up the network of arteries with all its bifurcations and vascular beds, then: as this primary wave travels along the arteries it will generate reflected waves from each bifurcation and from the peripheral vascular beds. all these small reflected waves return to the heart, summing to create a reflected wave as shown, starting even before the end of systole. Figure 2 Menu

71 Pressure aorta is sum of wave reflections at the Heart
So the pressure in the aortic root is the sum of the outgoing and reflected wave (the green wave). Note importantly how the reflected wave boosts the coronary artery perfusion pressure – the aortic root pressure – during diastole when over 95% of perfusion of the sub-endocardium takes place. Figure 3 Figure 3 Menu

72 What determines wave reflection at the heart?
The speed at which the outgoing and reflected waves travel is dependent on the stiffness of the arteries along which they are travelling. So if a person has stiffer arteries, the waves will travel out and back quicker, arriving earlier back at the heart (see graph). Figure 4 Figure 4 Menu

73 Pressure Wave Reflection at the Heart
Now when the outgoing and reflected waves are added there is a very different aortic root pressure waveform. There are three important clinical implications. Figure 5 Figure 5 Menu

74 Central vs brachial bloodpressure
Are antihypertensive drugs equal in lowering central bloodpressure? What determines central bloodpressure ? Clinical consequences of lower central bloodpressure and possible explanations?

75 Pressure Wave Reflection at the Heart Consequences
First, the central systolic pressure and central pulse pressure is increased. An increase in the central pulse pressure that drives cerebral blood flow increases stroke risk. NOTE: this change in central systolic pressure can occur without any changes occurring in peripheral cuff systolic pressure. Increased Central Pulse Pressure Figure 6 Menu

76 Fatal and non-fatal stroke
% 5.0 Atenolol  thiazide (No. of events 422) 4.0 3.0 Amlodipine  perindopril (No. of events 327) 2.0 HR = 0.77 (0.66­0.89) p = 1.0 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

77 Pressure Wave Reflection at the Heart
Second, there is an increase in left ventricular load (LV load). Increase in LV load accelerates increase in LV mass and increases risk of LV hypertrophy. The area under the pressure-time curve during systole is by definition LV load. This increase in LV Load (late systolic “afterload”) is shown by the black arrowed region. Increased LV Load D LVL Figure 7 Menu

78 Pressure Wave Reflection at the Heart
Third, the pressure that is perfusing the coronary arteries during the critical diastole period is reduced, increasing the risk of myocardial ischemias. Conclusion: Increasing arterial stiffness independently increases the risk of all three major cardiovascular outcomes. Decreased Coronary Artery Perfusion Pressure in Diastole Figure 8 Menu

79 Total coronary end point
% 10.0 Atenolol  thiazide (No. of events 852) 8.0 6.0 Amlodipine  perindopril (No. of events 753) 4.0 2.0 HR = 0.87 (0.79­0.96) p = 0.0 0.0 1.0 2.0 3.0 4.0 Years 5.0 Number at risk Amlodipine  perindopril Atenolol  thiazide

80 Amlodipine  perindopril
CV mortality % 3.5 Atenolol  thiazide (No. of events 342) 3.0 2.5 2.0 Amlodipine  perindopril (No. of events 263) 1.5 1.0 HR = 0.76 (0.65­0.90) p = 0.5 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Years Number at risk Amlodipine  perindopril Atenolol  thiazide

81 BP lowering drugs have different effects on central bloodpressure
Brachial BP Central BP (aorta) 2,3 SBP DBP SBP PP Decrease in BP (mmHg) -5 -10 -15 -20 Perindopril / indapamide (2 / 0,625 mg) Atenolol (50 mg) -25 Adjusted difference between group (mmHg) -6,02 p<0,001 -0,32 P= 0,715 -12,52 p< 0,001 -10,34 p< 0,01 Asmar R et al. Hypertension. 2001;38:

82 REASON study / AI decrease
P<0.001 Ao-AI (%) +1.8 -3.1 Knowing the importance of this marker, Preterax has been compared with atenolol in the REASON study and has demonstrated a significant improvement in AI. As AI depends principally on arterial stiffness and on the reflection site of the wave, and as we have just seen, Preterax and atenolol have a similar effect on PWV. A modification of the reflectance (microcirculation) can explain the variability of the responses regarding to the 2 drugs. Thus, Preterax could change reflective properties (wave reflection) due to an effect at the level of microcirculation (this effect is not observed with atenolol). This may suggest a possible differential advantage in terms of mortality, favoring Preterax. Perindopril-indapamide Atenolol P=0.112 P=0.002 Asmar R et al. Hypertens. 2001;38:

83 BP lowering drugs have different effects on structure small arteries
8 Arterial media-to-lumen ratio (%) 7.94 6 7.14 5.82 5.96 6.79 4 Normotensive Before After Before After Normotensive n=25 Perindopril n=13 Atenolol n=12 Effect of antihypertensive treatment on small arteries of patients with previously untreated essential hypertension was evaluated with perindopril and atenolol. Gluteal biopsies were taken before and after treatment under local anesthetic. A significant change in the media:lumen ratio after the treatment with perindopril was obvious, in contrast to atenolol and besides the similar BP reduction obtained. Mean BP (mmHg) 90 122 101** 126 98** Lumen ø (µm) 237 208 247*ii 222 208 vs before *P <0.05. **P < vs atenolol iiP < 0.01 Thybo NK, et al. Hypertension 1995; 25:

84 BP lowering drugs have different effects on structure large arteries
Double-blind randomized study 41 hypertensive patients (DBP : mmHg) Perindopril : n = 20 - Diuretic : n = 21) 6-week placebo run-in 6-month study carotid artery elasticity (% improvement) 5 10 15 20 1 16* p < 0.05 *p<0.05 versus baseline HCTZ 25 mg + amiloride 2,5 mg Perindopril 4 mg Kool M.J. Van Bortel L.M. et al. J Hypertens 1995 ; 13 :

85 CAFE Study Conclusions
Brachial blood pressure overestimated the hemodynamic benefit of atenolol ± thiazide-based treatment and underestimated the benefit of amlodipine ± perindopril-based treatment on central aortic pressures and hemodynamics Central aortic pressure may be an important independent determinant of clinical outcomes Results of the CAFE study suggest that the “central aortic blood pressure hypothesis” is a plausible mechanism to explain the better clinical outcomes for hypertensive patients treated with amlodipine ± perindopril-based therapy in ASCOT


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