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B.Dahlof (Co-chair), P.Sever (Co-chair), N. Poulter (Secretary) H. Wedel (Statistician), G. Beevers, M. Caulfield, R. Collins S. Kjeldsen, A. Kristinsson,

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Presentation on theme: "B.Dahlof (Co-chair), P.Sever (Co-chair), N. Poulter (Secretary) H. Wedel (Statistician), G. Beevers, M. Caulfield, R. Collins S. Kjeldsen, A. Kristinsson,"— Presentation transcript:

1 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. OBrien, J. Östergren, on behalf of the ASCOT Investigators A randomised controlled trial of the prevention of CHD and other vascular events by BP and cholesterol lowering in a factorial study design

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 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) Primary Objective

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 Study design atenolol ± bendroflumethiazide amlodipine ± perindopril 19,257 hypertensive patients PROBE design ASCOT-BPLA 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 perindopril 4-8 mg bendroflumethiazide-K mg doxazosin GITS 4-8 mg add additional drugs, eg, moxonidine/spironolactone add

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

8 Study power and recruitment (Feb 1998-May 2000) Relative additional benefit (ITT) 16% Significance level5% Power 80% Estimated sample size18,000 Persons with events 1150 TOTAL RECRUITED 19,257 POWER: PRIMARY END POINT

9 Baseline characteristics amlodipine perindopril atenolol thiazide Demographics and clinical characteristics n = 9639 n = 9618 Woman2258 (23.4%) 2257 (23.5%) White9187 (95.3%) 9170 (95.3%) Current smoker3168 (32.9%) 3110 (32.3%) Age (years) 63.0 (8.5) 63.0 (8.5) SBP (mm Hg) (18.1) (18.0) DBP (mm Hg) 94.8 (10.4) 94.5 (10.4) Heart rate (bpm) 71.9 (12.7) 71.8 (12.6) BMI (kg/m 2 ) 28.7 (4.6) 28.7 (4.5) Drug therapy Previous antihypertensive treatments (19.1%) 1825 (19.0%) (44.4%) 4283 (44.5%) (36.5%) 3510 (36.5%) Lipid-lowering therapy1046 (10.9%) 1004 (10.4%) Aspirin1851 (19.2%) 1837 (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.

11 Statistical methods Based on an intention-to-treat analysis Time to first primary event Log-rank procedure and Coxs Proportional Hazards were used to calculate confidence intervals Cumulative incidence curves were generated using the Kaplan-Meier method Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

12 All patients in ASCOT have hypertension plus 3 risk factors for CHD Patients with risk factor (%) 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 ASCOT patient population risk factor profile 100

13 trial design 19,342 randomised to antihypertensive therapy 85 excluded before end of study due to irregularities 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) 19,257 randomised

14 Systolic and diastolic blood pressure mm Hg Time (years) Baseline atenolol thiazide amlodipine perindopril Mean difference 1.9 Last visit Mean difference 2.7 SBP DBP

15 Mean proportion of time on antihypertensive medication by treatment group Year 1All Study Randomised to Amlodipine Amlodipine Perindopril Amlodipine + perindopril Randomised to atenolol Atenolol Bendroflumethiazide Atenolol + bendroflumethiazide

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

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

18 Primary end point + coronary revascularisation procedures Number at risk Amlodipine perindopril Atenolol thiazide % Years HR = 0.86 (0.77­0.96) p = Atenolol thiazide (No. of events 688) Amlodipine perindopril (No. of events 596) 8.0

19 Number at risk Amlodipine perindopril Atenolol thiazide Years Amlodipine perindopril (No. of events 753) Atenolol thiazide (No. of events 852) HR = 0.87 (0.79­0.96) p = % Total coronary end point

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

21 Total CV events and procedures Number at risk Amlodipine perindopril Atenolol thiazide Years Amlodipine perindopril (No. of events 1362) Atenolol thiazide (No. of events 1602) HR = 0.84 (0.78­0.90) p < %

22 CV mortality Number at risk Amlodipine perindopril Atenolol thiazide Years Amlodipine perindopril (No. of events 263) Atenolol thiazide (No. of events 342) HR = 0.76 (0.65­0.90) p = %

23 All-cause mortality Number at risk Amlodipine perindopril Atenolol thiazide Years HR = 0.89 (0.81­0.99) p = % Amlodipine perindopril (No. of events 738) Atenolol thiazide (No. of events 820)

24 Fatal and non-fatal heart failure Number at risk Amlodipine perindopril Atenolol thiazide HR = 0.84 (0.66­1.05) p = Amlodipine perindopril (No. of events 134) Atenolol thiazide (No. of events 159) % Years 1.8

25 Unstable angina Number at risk Amlodipine perindopril Atenolol thiazide HR = 0.68 (0.51­0.92) p = % Amlodipine perindopril (No. of events 73) Atenolol thiazide (No. of events 106) Years

26 Chronic stable angina HR = 0.98 (0.81­1.19) p = % Years Number at risk Amlodipine perindopril Atenolol thiazide Amlodipine perindopril (No. of events = 205) Atenolol thiazide (No. of events = 208)

27 Peripheral arterial disease HR = 0.65 (0.52­0.81) p = Number at risk Amlodipine perindopril Atenolol thiazide % Years Amlodipine perindopril (No. of events = 133) Atenolol thiazide (No. of events = 202)

28 Life-threatening arrhythmias Years HR = 1.07 (0.62 ­1.85) p = Number at risk Amlodipine perindopril Atenolol thiazide Amlodipine perindopril (No. of events = 27) Atenolol thiazide (No. of events = 25) %

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

30 New-onset diabetes mellitus Number at risk Amlodipine perindopril Atenolol thiazide Years Amlodipine perindopril (No. of events = 567) Atenolol thiazide (No. of events = 799) HR = 0.70 (0.63­0.78) p < %

31 CV death + MI + stroke Years Amlodipine perindopril (No. of events = 796) Atenolol thiazide (No. of events = 937) HR = (0.76­0.92) p < Number at risk Amlodipine perindopril Atenolol thiazide %

32 Summary of all end points The area of the blue square is proportional to the amount of statistical information Amlodipine perindopril better Atenolol thiazide better 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 2.00 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 ( )

33 Total CV events and procedures among subgroups The area of the black square is proportional to the amount of statistical information Amlodipine perindopril betterAtenolol thiazide better 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

34 Total CV events and procedures among subgroups The area of the black square is proportional to the amount of statistical information Amlodipine perindopril betterAtenolol thiazide better 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 p value < < < < < < Heterogeneity p

35 Adverse events leading to treatment discontinuation Adverse event Amlodipine perindopril (%) Atenolol thiazide (%) Total2358 (24.5)2402 (25.0) Serious162 (1.7)254 (2.6)* * p<0.0001

36 Adverse events Adverse event* Amlodipine perindopril n (%) Atenolol thiazide n (%) p-value Bradycardia34(0.4)536(6)< Chest pain740(8)849(9) Cough1859(19)782(8)< Diarrhoea377(4)548(6)< Dizziness1183(12)1555(16)< Dyspnoea599(6)987(10)< Eczema493(5)383(4) Erectile dysfunction556(6)707(7)< Fatigue782(8)1556(16)< Joint swelling1371(14)308(3)< Lethargy202(2)525(6)< Oedema peripheral2188(23)588(6)< Peripheral coldness81(1)579(6)< Vertigo642(7)745(8) * 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< 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<0.0001

40 Endpoints evaluated 1.Primary endpoint + coronary revascularisation (coronary events) 2.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 SBPDBP 0-6 months year years years years years > 5 years All study Hazard ratio Amlodipine perindopril better Atenolol thiazide better Time interval Accumulated differences (mmHg) Atenolol thiazide - Amlodipine perindopril SBPDBP 0-6 months year years years years years All study 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 SBPDBP 0-6 months year years years years years > 5 years All study Time interval Accumulated differences (mmHg) Atenolol thiazide - Amlodipine perindopril SBPDBP 0-6 months year years years years years All study Amlodipine perindopril better Atenolol thiazide better Hazard ratio Hazard ratio Amlodipine perindopril better Atenolol thiazide better

44 Serial mean matching: Methods SBP % Take Amlodipine ± perindopril cohort at each of five time points plus baseline Amlodipine ± perindopril (all patients) Select atenolol ± thiazide person closest to mean after randomisation Mean Add others sequentially to maintain group SBP matching Atenolol ± thiazide matched subset NB: n> 7500 (86%) 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 ( ) 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 HRp-value Unadjusted Systolic BP Diastolic BP Mean BP* Pulse pressure Heart rate Glucose HDL cholesterol Triglycerides Creatinine Potassium Weight * Mean BP = (SBP/DBP)/2

47 Hazard ratios for treatment effect on stroke events adjusted for accumulated mean levels of variables that differed Fatal and non-fatal stroke HRp-value Unadjusted Systolic BP Diastolic BP Mean BP* Pulse pressure Heart rate Glucose HDL cholesterol Triglycerides Creatinine Potassium Weight * Mean BP = (SBP/DBP)/2

48 Impact on the treatment effect on coronary events after adjustment for BP and all variables that differed Hazard ratio 95% CI Unadjusted SBP SBP + covariates SBP + DBP + covariates MBP** + covariates PP + covariates Hazard ratio 95% CI Unadjusted SBP SBP + covariates SBP + DBP + covariates MBP** + covariates PP + covariates p-value Amlodipine perindopril better Atenolol thiazide better ** MBP = (SBP+DBP)/2 Hazard ratio 95% CI Unadjusted SBP SBP + covariates SBP + DBP + covariates MBP** + covariates PP + covariates

49 Impact on the treatment effect on stroke events after adjustment for BP and all variables that differed Hazard ratio 95% CI Unadjusted Mean BP SBP + covariates SBP + DBP + covariates MBP** + covariates PP + covariates Hazard ratio 95% CI Unadjusted Mean BP SBP + covariates SBP + DBP + covariates MBP** + covariates PP + covariates p-value Amlodipine perindopril better Atenolol thiazide better ** MBP = (SBP+DBP)/2 Hazard ratio 95% CI Unadjusted Mean BP SBP + covariates SBP + DBP + covariates MBP** + covariates PP + covariates

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) Endpoint Amlodipine perindopril + statin Atenolol thiazide + placebo Relative risk reduction Fatal MI and non-fatal CHD % Fatal and non-fatal stroke % Rates / 1000 patient years

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

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 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) CAFE : Background (2)

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 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 1042 assessed on an intention- to-treat basis 1038 complete information (997 alive, 41 dead) 1 subject incomplete information, withdrawn consent 1031 assessed on an intention- to-treat basis 1030 complete information (989 alive, 41 dead) 126 excluded due to heart rate irregularity/poor waveforms

62 Baseline Demographics (1) Atenolol- based n=1031 Amlodipine- based n=1042 Atenolol-based n=9639 Amlodipine- based n=9618 Women189 (18.3%)208 (20%)2257 (23.5%)2258 (23.4%) Age (years)62.6 (8.3)62.9 (8.2)63.0 (8.5) White886 (85.9%)892 (85.6%)9170 (95.3%)9187 (95.3%) Current smoker251 (24.3%)267 (25.6%)3109 (32.3%)3168 (32.9%) SBP mm Hg159.9 (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/m 2 )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) (38.7)224.3 (42.5)228.2 (42.5) LDL-cholesterol (mg/dL)143.1 (34.8) (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)159.4 (88.6) Glucose (mg/dL)110 (38) 112 (38) Creatinine (mg/dL)1.08 (0.18)1.09 (0.19) 1.09 (0.18) CAFE ASCOT

63 Baseline Demographics (2) Atenolol-based n=1031 Amlodipine- based n=1042 Atenolol-based n=9639 Amlodipine- based n=9618 Medical history Prior stroke/TIA76 (7.4%)62.9 (8.2)63.0 (8.5) Diabetes252 (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 factors3.7 (0.9) Drug therapy BP treatment naive109 (10.6%)100 (9.6%)1825 (19%)1841 (19.1%) Lipid-lowering therapy120 (11.6%)120 (11.5%)1004 (10.4%)1046 (10.9%) Aspirin use244 (23.7%)274 (26.3%)1837 (19.1%)1851 (19.2%) CAFE ASCOT

64 Mean Proportion of Time (%) on BP Lowering Medication by Treatment Group* Year 1All study Randomized to Amlodipine Amlodipine Perindopril Amlodipine + perindopril Randomized to Atenolol Atenolol Bendroflumethiazide Atenolol + bendroflumethiazide * From time of randomization into ASCOT

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

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

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 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 Pressure Wave Reflection at the Heart What is it? Menu Figure 1

70 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. Menu Figure 2 Pressure Wave Reflection at the Heart What is it?

71 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 Pressure aorta is sum of wave reflections at the Heart Menu Figure 3

72 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 What determines wave reflection at the heart? Menu Figure 4

73 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 Pressure Wave Reflection at the Heart Menu Figure 5

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 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. Pressure Wave Reflection at the Heart Consequences Increased Central Pulse Pressure Menu Figure 6

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

77 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. Figure 7 Pressure Wave Reflection at the Heart LVL Increased LV Load Menu

78 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. Figure 8 Pressure Wave Reflection at the Heart Decreased Coronary Artery Perfusion Pressure in Diastole Menu

79 Number at risk Amlodipine perindopril Atenolol thiazide Years Amlodipine perindopril (No. of events 753) Atenolol thiazide (No. of events 852) HR = 0.87 (0.79­0.96) p = % Total coronary end point

80 CV mortality Number at risk Amlodipine perindopril Atenolol thiazide Years Amlodipine perindopril (No. of events 263) Atenolol thiazide (No. of events 342) HR = 0.76 (0.65­0.90) p = %

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

82 -3.1 Ao-AI (%) +1.8 Perindopril- indapamide Atenolol P=0.002 P=0.112 REASON study / AI decrease P<0.001 Asmar R et al. Hypertens. 2001;38:

83 Thybo NK, et al. Hypertension 1995; 25: vs before *P <0.05. **P < vs atenolol ii P < 0.01 Mean BP (mmHg) Lumen ø (µm) **12698** * ii P < 0.01 P < 0.05 NS NormotensiveBefore After Arterial media-to-lumen ratio (%) Perindopril n=13 Atenolol n=12 Normotensive n=25 BP lowering drugs have different effects on structure small arteries

84 HCTZ 25 mg + amiloride 2,5 mg Perindopril 4 mg carotid artery elasticity (% improvement) * p < 0.05 *p<0.05 versus baseline Double-blind randomized study 41 hypertensive patients (DBP : mmHg) Perindopril : n = 20 - Diuretic : n = 21) 6-week placebo run-in 6-month study BP lowering drugs have different effects on structure large arteries 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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