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TREATMENT of HYPERTENSION in the 21 st Century Sir George Pickering Lecture Peter Sever

TREATMENT of HYPERTENSION in the 21 st Century Sir George Pickering Lecture Peter Sever International Centre for Circulatory Health Imperial College London. Sir George Pickering Professor of Medicine St Mary’s Hospital Medical School 1939 Regius Professor of Medicine Oxford 1956.

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TREATMENT of HYPERTENSION in the 21 st Century Sir George Pickering Lecture Peter Sever

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  1. TREATMENT of HYPERTENSION in the 21st Century Sir George Pickering Lecture Peter Sever International Centre for Circulatory Health Imperial College London

  2. Sir George Pickering Professor of Medicine St Mary’s Hospital Medical School 1939 Regius Professor of Medicine Oxford 1956

  3. Pickering: “High Blood Pressure” 1955Terminology Hypertension – not a well chosen word, a bastard of Greek and Latin parentage and signifying not high blood pressure but over-much stretching. The use of the term has lead to the practice of distinguishing between normal pressure and hypertension, and thus by easy stages to the assumption that those subjects with hypertension differ qualitatively from the rest of mankind

  4. Platt’s hypothesis-Pickering’s data ! Platt’s hypothesis Pickering’s data

  5. If Pickering had had access to blood pressure responses to different classes of antihypertensive drugs, the unimodality hypothesis would have been much more persuasive

  6. The frequency distribution of changes in diastolic blood pressure (DBP) produced by 3 drugs DBP placebo– atenolol, mmHg DBP placebo – lisinopril, mmHg 16 16 12 12 Count Count 8 8 4 4 0 0 20 10 0 -10 -20 -30 -40 -10 -30 -40 20 10 0 -20 16 DBP placebo – nifedipine, mmHg 12 Count 8 Atwood et al J Hypertens 1994; 12:1053 4 0 20 10 0 -10 -20 -30 -40

  7. Treatment of Hypertension

  8. Does the magnitude of response to an antihypertensive drug inform on the mechanism(s) involved in blood pressure elevation ?

  9. Two important observations :Blood pressure responses toSpironolactone and toRenal denervation in subjects with resistant hypertension

  10. Frequency distribution of change in SBP after spironolactone or renal denervation The Symplicity HTN 2 Trial ASCOT Simulated FD curve Based on reported mean +/-SD in SBP Mean  SBP: -21.87±21.27 mmHg Mean  SBP: -32±23 mmHg Chapman et al. Hypertension. 2007 ;49:839-45. Symplicity HTN-2 Investigators. Lancet 2010; 376:1903-09

  11. Placebo corrected SBP response to monotherapy ( ) and dual therapy ( ) meta analysis of 42 trials Wald DS et al. Am J Med 2009; 122:290-300

  12. Frequency distribution of change in SBP from baseline among ASCOT monotherapy users (untreated at baseline) Mean  SBP: -18.81±16.93 mmHg Mean  SBP: Atenolol: -17.35±18.36 mmHg; Amlodipine: -20.16±15.37 mmHg

  13. Frequency distribution of change in SBP from baseline among ASCOT monotherapy users (untreated at baseline) Note Placebo response from randomised controlled trials in hypertensive subjects estimated to be approx 10mmHg systolic pressure Mean  SBP: Atenolol: -17.35±18.36 mmHg; Amlodipine: -20.16±15.37 mmHg

  14. Frequency distribution of change in SBP after second drug ( BFZ+K or Perindopril) therapy Mean  SBP: BFZ+K: -9.24 mmHg; Perindopril: -6.29 mmHg

  15. Frequency distribution of change in SBP after third drug (doxazosin) therapy Mean  SBP: -11.68±18.81 mmHg Mean  SBP: Atenolol group: -13.38±19.89 mmHg; Amlodipine group: -9.39±16.98 mmHg

  16. Frequency distribution of change in SBP after spironolactone therapy Mean  SBP: -21.87±21.27 mmHg Mean  SBP: Atenolol group: -22.99±21.46 mmHg; Amlodipine group: -18.51±20.33 mmHg

  17. Frequency distribution of change in SBP after spironolactone therapy Note greater response in the atenolol/thiazide arm. Effect not influenced by concomitant diuretic use Mean  SBP: atenolol group: -22.99 mmHg; amlodipine group: -18.51 mmHg

  18. Blood pressure response to renal denervation: The Symplicity HTN 2 Trial Symplicity HTN-2 Investigators .Lancet 2010;376:1903-1909

  19. Summary Spiro Blocking two apparently different physiological systems in patients with drug resistant hypertension leads to substantial reductions in blood pressure. These reductions in blood pressure far greater than expected from renal efferent sympathetic blockade or the action of aldosterone blockade on sodium and water homeostasis Do these observations highlight two separate phenotypes with resistant hypertension - volume overload and excess vascular resistance ? Denervation Denervation

  20. Resistant hypertension : Haemodynamics After Brown M. BHS Guideline on Resistant Hypertension ( unpublished)

  21. Resistant hypertension : Key features Muscle sympathetic nerve activity and increasing blood pressure Blunted natriuresis Increased extracellular volume Activation of RAAS Increased renal sympathetic nerve activity Increased sodium reabsorption severe mild-moderate hypertensive normotensive Grassi G et al. Exp Physiol 2010;95:581-586

  22. Response to spironolactone and to denervationOr are these observations providing a clue to an important interaction between sodium homeostasis and CNS activation which may be relevant not only in the context of resistant hypertension but also perhaps , importantly, more generally in the context of raised blood pressure

  23. Spironolactoneactions include :- • Lowers sympathetic nervous system activity in older hypertensive subjects ( lowers plasma noradrenaline and reduces 3H –NA release rates - not seen with thiazides ) • Binds to aldosterone sensitive mineralocorticoid receptors in the NTS, the anterior hypothalamus and other brain stem centres including the RVLM and PVN (Geerling and Loewy 2009) • Enhances parasympathetic tone and may decrease sympathetic activity Wray and Supiano 2010

  24. Spironolactone

  25. Renal denervation • Blocks renal efferent sympathetic nerve activity • Blocks renal afferent nerve activity • Induces substantial sodium and water loss

  26. Genetic Environmental eg Salt Mosaic 2011 Haemodynamics Renal BP Humoral Anatomical Intrauterine programming Adaptive Endocrine Neural Modified from Page 1959

  27. Implication of these observations in resistant hypertension to pathophysiology of “essential” hypertensionLinkage of dietary salt and the CNS to elevated blood pressure

  28. Interaction hypothesis supported by:- Experimental models of hypertension - SHR and salt loading Koepke et al.Hypertension 1985; 7: 357-363 • DOCA salt model and stress Koepke et al. Am J Physiol. 1986; 251: R289-294 • Dietary salt enhances excitability and increases the gain of sympathetic-regulatory neurons in RVLM in salt sensitive animal models. Stocker et al. Physiol.Behav. 2010;100: 519-524. Stress, sodium retention and BP elevation in normotensive human subjects with family history of hypertension Light et al.Science 1983: 220: 429-43 Linked to genetic polymorphism of the alpha 2 adrenoceptor Finlay et al. J. Appl Phys 2004; 96: 2231-2239 Longitudinal migration study Poulter et al. BMJ. 1990 Apr 14;300: 967-72

  29. Kenyan Luo Migration Study modified from Poulter et al. BMJ. 1990 Apr 14;300: 967-72 SBP levels at 0-24 months 130 migrants 120 mmHg non-migrants Mean pre-migration blood pressure 110 100 0 3 6 12 18 24 months Males DBP levels at 0-24 months 70 migrants mmHg 60 Mean pre-migration blood pressure non-migrants 50 0 3 12 18 6 24 months

  30. Sever et al In Concepts in hypertension Springer-Verlag 1989 p 55-66

  31. Body weight, pulse and urinary NaK ratios at 0-24 months Males Body weight (kg) Pulse (bpm) Urinary NaK ratio 61.0 5.0 75 57.5 69 3.5 54.0 63 2.0 0 24 12 0 0 24 3 12 24 12 18 6 3 3 18 6 18 6 Controls Migrants Females Body weight (kg) Pulse (bpm) Urinary NaK ratio 61.0 5.0 75 69 57.5 3.5 63 2.0 54.0 0 24 12 0 0 24 24 12 3 12 18 3 6 3 18 18 6 6 Poulter et al. BMJ. 1990 Apr 14;300: 967-72

  32. Hypothesis required to incorporate:- • Early blood pressure elevation • Rapid increase in body weight ( not explained by increase in dietary calorie intake) • Increase in dietary sodium • Increase in heart rate

  33. Neuronal genotype (s) - influences neuronal responses to plasma/CSF sodium Renal genotype(s)-influence tubular reabsorption of sodium and/or renal afferent nerve responses to sodium load

  34. Guyton hypothesis *Impaired if prevented by: Angiotensin II Renal sympathetic nerve activity Aldosterone Reduced renal mass

  35. The way forward :Integrative physiology Further understanding of genetic and environmental factors, the basis of their interaction and their influence on the neuro/humoral/renal/vascular mechanisms that are likely to be involved in the multi-factorial, multi-genetic nature of hypertension.

  36. Improved methods to understand the integration of biological systems • Requires more quantitative approaches and modelling of cardiovascular system dynamics • Requires advances in medical imaging technology to permit non-invasive studies of the brain, vasculature and kidney in the whole animal/human. • A fully integrative mathematical model is essential for the complete analysis of currently available data • Data needs to be acquired from long-term minimally invasive observations of cardiovascular variables in humans and animal models under a variety of behavioural and environmental conditions.

  37. Challenges to the scientific community Need for teams of researchers to design studies that draw upon expertise in the fields of genomics, proteomics, informatics, statistical genetics, cellular and integrative physiology, mathematics and computer science. • Systems biology is the delineation of the elements in a biological system and the analysis of their interactions after genetics or environmental perturbation. • The goal of systems biology is to explain the systems emergent properties (phenotypic transformation) that are absent when the elements of the system are studied in isolation, but are only present when multiple elements within a system interact • Systems biology should be hypothesis driven, quantitative, integrative and iterative. • Bioinformatics and computational biology is necessary to resolve the complex interrelationships between the multiple organs and systems involved not only in blood pressure regulation but also in the consequential impact of blood pressure and other risk factors on target organs

  38. Hypertension treatment The ASCOT Legacy

  39. ASCOT History • 1988/9 European Blood Pressure Group- discussion on unmet needs in hypertension research • 1991 British Hypertension Society Working Party formed; produced initial trial design but no funding • 1993 Furberg and the CCB controversy • 1993 NHLBI agree to fund ALLHAT • 1995 Joint discussions between UK, Sweden and Pfizer. • 1996 ASCOT announcement and Steering Committee established

  40. ASCOT: Rationale • Insufficient outcome data on newer types of blood pressure lowering agents • No data on the evaluation of specific combination treatment regimens • Shortfall of CHD prevention using standard therapy • Need to evaluate multiple risk factors in the prevention of CHD • No data on the benefits of lipid lowering among hypertensives

  41. 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 Sever et al J. Hypertension. 2001;19:1139

  42. Lipid-lowering arm

  43. ASCOT-LLA : Nonfatal MI and Fatal CHD Atorvastatin 10 mg Number of events 100 Placebo Number of events 154 36% reduction HR = 0.64 (0.50-0.83) p=0.0005 Relative risk reductions independent of baseline cholesterol Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

  44. ASCOT-LLA CHD events :early benefits * • Risk Reduction Event Rate • (%)AtorvastatinPlacebo • 83 2.4 14.2 • 67 5.5 16.6 • 48 7.5 14.3 • 45 6.6 12.0 • 38 5.9 9.5 • 36 6.0 9.4 Censoring Time Hazard Ratios (95% CI) 30 days 90 days 180 days 1 Year 2 Years End of Study * Per 1000 patient years Atorvastatin better Placebo better

  45. 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

  46. Blood Pressure-lowering arm

  47. 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

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