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PS Sever, PM Rothwell, SC Howard, JE Dobson, B Dahlöf, H Wedel, NR Poulter, for the ASCOT Investigators

The Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm (ASCOT-BPLA) Blood Pressure Variability and Cardiovascular Outcomes. PS Sever, PM Rothwell, SC Howard, JE Dobson, B Dahlöf, H Wedel, NR Poulter, for the ASCOT Investigators.

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PS Sever, PM Rothwell, SC Howard, JE Dobson, B Dahlöf, H Wedel, NR Poulter, for the ASCOT Investigators

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  1. The Anglo-Scandinavian Cardiac Outcomes Trial –Blood Pressure Lowering Arm (ASCOT-BPLA)Blood Pressure Variability and Cardiovascular Outcomes PS Sever, PM Rothwell, SC Howard, JE Dobson, B Dahlöf, H Wedel, NR Poulter, for the ASCOT Investigators International Centre for Circulatory Health, Imperial College London and Stroke Prevention Research Unit, University of Oxford

  2. A randomised controlled trial of the prevention of CHD and other vascular events by BP and cholesterol lowering in a factorial study design

  3. Investigator-led, multinational randomised controlled trial conducted in hypertensive patients, 40 -79 yrs, with no prior history of CHD, but with 3 additional cardiovascular risk factors (male sex, > 55 yrs, smoking etc ) Study design 19,257 hypertensive patients ASCOT-BPLA Stopped after 5.5 yrs PROBE design atenolol ± bendroflumethiazide amlodipine ± perindopril

  4. Treatment algorithm to BP targets < 140/90 mmHg or < 130/80 mmHg in patients with diabetes amlodipine 5-10 mg atenolol 50-100 mg add add bendroflumethiazide-K 1.25-2.5 mg perindopril 4-8 mg add doxazosin GITS 4-8 mg add additional drugs, eg, moxonidine/spironolactone Median follow up was for 5.5 years

  5. Baseline characteristics

  6. Systolic and diastolic blood pressure amlodipine  perindopril atenolol  bendroflumethiazide 180 164.1 SBP 160 163.9 Mean difference 2.7 137.7 140 136.1 Blood pressure (mmHg) 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 Follow-up (years)

  7. ASCOT-BPLA: summary of all endpoints 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 (0.63-0.78) 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 (excl. silent) + fatal CHD Total coronary endpointTotal CV events 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 endpoint + 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. Conclusions • Amlodipine  perindopril-based therapy conferred an advantage over atenolol  thiazide-based therapy on all major CV endpoints, all-cause mortality and new-onset diabetes • Additional statistical analyses demonstrated that adjusting for blood pressure differences between treatment groups early on in the trial, did not account for the observed differences in cardiovascular outcomes

  9. ASCOT-Blood pressure variability: methods(based on over 1 million BP readings) • Of 19,257 patients, 18,530 had ≥ 2 follow-up visits (median = 10) from 6 months onwards until the end of the trial • 3 blood pressure measurements were recorded at each visit, using standardised techniques, at 6 monthly intervals for a median follow up of 5.5 years • From 6 months onwards there were 350 strokes and 704 coronary events (non-fatal MI, fatal CHD, new onset angina, non-fatal and fatal heart failure) in the atenolol-based group and 279 and 611 respectively in the amlodipine-based group

  10. Blood pressure variability: methods • Visit-to-visit variability of SBP and DBP during follow-up, from 6 months after randomisation to the end of the trial, were expressed as the standard deviation (SD), coefficient of variation (CV), and a transformation of SD uncorrelated with mean BP (variability independent of mean – VIM) • Within-visit variability was expressed as the SD of the three measurements taken at each visit averaged across all follow-up visits • Among 1905 patients, mean BP and variability were also determined with annual 24 hour ambulatory monitoring (ABPM) • Cox models were used to determine associations with risks of vascular events during follow-up, and whether an effect on variability in BP could account for the reduction in events in the amlodipine group

  11. Means and measures of variability of clinic SBP by treatment group Parameters calculated using all measurements from 6 months onwards

  12. Means and measures of variability of clinic DBP by treatment group Parameters calculated using all measurements from 6 months onwards

  13. Visit-to-visit mean systolic blood pressure expressed in deciles, hazard ratios (95% CI) and number of stroke and coronary events in each decile Mean SBP Coronary risk Stroke risk

  14. Stroke and coronary risk expressed by decile of measure of visit-to-visit SBP variability Coronary Risk Stroke Risk Atenolol Standard deviation of SBP Amlodipine Coefficient of variation of SBP Variation independent of mean SBP Decile of measure Decile of measure

  15. Group distribution (SD and CV) of measures of SBP at baseline and at each follow-up visit in the two treatment groups

  16. Stroke risk and coronary risk expressed by decile of within-visit SBP variability Stroke risk (HR, 95% CI) Number of patients in each decile of within-visit SD SBP Coronary risk (HR, 95% CI)

  17. Average within-visit CV in the two treatment groups during follow-up

  18. Hazard ratios (95% CI) for the effect of treatment (amlodipine versus atenolol) on risk of stroke Parameters calculated using all BP measurements from 6 months onwards. Mean, SD, CV, and VIM are entered into the model as deciles

  19. Hazard ratios (95% CI) for the effect of treatment (amlodipine versus atenolol) on risk of coronary events Parameters calculated using all BP measurements from 6 months onwards. Mean, SD, CV, and VIM are entered into the model as deciles

  20. Ambulatory blood pressure monitoring • 1905 patients had an average of 3.25 recordings from 6 months onwards • Daytime SBP slightly higher but night-time SBP slightly lower on amlodipine-based treatment • Morning surge similar on both treatments and only weakly correlated with BP visit-to-visit variability • Intra ABPM coefficient of variation of SBP correlated with visit-to-visit variability in clinic SBP • atenolol group, r = 0.38 • amlodipine group, r = 0.29, p < 0.0001 for both groups • Intra ABPM variability in daytime SBP predicted both stroke and coronary events (but less so than visit-to-visit variability)

  21. Summary • Mean BP in trial has minimal effect on stroke outcome and no effect on CHD outcome • Various measures of visit-to-visit BP variability (SD, coefficient of variation and variation independent of mean BP) are powerful predictors of both stroke and CHD outcomes • Other measures of variability (within-visit variability and variability assessed by ABPM) also predict cardiovascular outcomes but less than visit-to-visit variability • Amlodipine reduces variability compared with atenolol • Variability increased with age, diabetes, smoking, and in those with established vascular disease • Adjusting for BP variability completely explains differences in stroke and CHD outcomes between amlodipine-based and atenolol-based treatment in ASCOT

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