Research and Trials within the BHS Morris J Brown William Harvey - - PowerPoint PPT Presentation
Research and Trials within the BHS Morris J Brown William Harvey Research Institute Queen Mary University of London Topics PATHWAYs Recent (summary of P1, P2, P3) Present (mechanisms sub-studies, mainly P2) Future (GWAS,
Morris J Brown
William Harvey Research Institute Queen Mary University of London
– Recent (summary of P1, P2, P3) – Present (mechanisms sub-studies, mainly P2) – Future (GWAS, Mendelian Randomisation, P4?)
– 11C-metomidate PET CT vs Adrenal Vein Sampling (‘MATCH’) – Endoscopic radiofrequency ablation of adrenal adenomas (‘FABULAS’)
PATHWAY Steering Committee
Morris J Brown – Chairman Gordon McInnes, Thomas MacDonald Peter Sever Bryan Williams Isla MacKenzie David J Webb Sandosh Padmanabhan Mark Caulfield Jackie Salsbury – Co-
J Kennedy Cruickshank Steve Morant - Statistician Ian Ford
PATHWAY Executive Committee
Morris J Brown (Chairman): University of Cambridge Thomas MacDonald: University of Dundee Bryan Williams: University College London
PATHWAY Study Sites and Investigators
Cambridge: Anne Schumann, Jo Helmy, Carmela Maniero, Timothy J Burton, Ursula Quinn, Lorraine Hobbs, Jo Palmer, Ixworth: John Cannon, Sue Hood Birmingham: (2 sites) Una Martin, Richard Hobbs, Rachel Iles Kings College London: Krzysztof Rutkowski Dundee: Alison R McGinnis, JG Houston, Evekyn Findlay , Caroline Patterson, Imperial College London: Judith Mackay, Simon A McG Thom, Candida Coghlan Leicester: Adrian G Stanley, Christobelle White, Peter Lacy, Pankaj Gupta, Sheraz A Nazir, Caroline J. Gardiner-Hill Manchester: Handrean Soran, See Kwok, Karthirani Balakrishnan Edinburgh: Vanessa Melville, Iain M MacIntyre Norwich: Khin Swe Myint, Judith Gowlett St Barts London: David Collier, Nirmala Markandu, Manish Saxena, Anne Zak, Enamuna Enobakhare Glasgow: Scott Muir, Linsay McCallum
Data Centre and Monitor
Robertson Centre for Biostatistics, University of Glasgow Sharon Kean, Richard Papworth, Robbie Wilson, Ian Ford Monitor: Elizabeth Sprunt
£2.6M award, Nov 2007, to BHS for 3 studies investigating rational treatment algorithms: ‘PATHWAY’ =
Pathway 1
Could aggressive early treatment of raised blood pressure prevent subsequent treatment resistance?
Pathway 2
Is resistant hypertension usually due to excessive Na+ retention? Is spironolactone superior to other potential add on drugs?
Pathway 3 Are K+ sparing diuretics neutral or beneficial in their effect on glucose tolerance?
Com
ersus seq sequential mon
apy for
initial tr treatment of
ypertension (P (PATHWAY-1)
N=605
Home systolic BP (mmHg) 120 125 130 135 140 145 150 155 Weeks from baseline
4 8 12 16 24 32 38 44 52 Phase 1 Phase 2 Phase 3
Combination therapy Monotherapy, HCTZ first Monotherapy, losartan first
4.9mmHg p < 0.001 +1.2mmHg p=0.13 8mmHg 2.9mmHg
20 40 60 80 100
Phase 1 Phase 2 Phase 3 %
HBP< 135/85mmHg or Clinic BP < 140/90mmHg
‘initial combination trumps initialled monotherapy’
Home systolic BP (mmHg) 125 130 135 140 145 150 Renin tertile Bottom Middle Top
HCTZ Losartan Combination
Randomised initial treatment HCTZ Losartan lue Difference (95% CI) p-value Difference (95% CI) p-value 4·31 (-2·26,6·35) <·001
<·001
0·001
0·032 4·96 (2·12,7·80) <·001
0·008 Top vs Bottom renin tertile(1) Aged over 55 vs 55 and under(1) Renin (per 10 fold increase)
Spironolactone 25 – 50mg o.d. Doxazosin MR 4 – 8mg o.d. Bisoprolol 5 – 10mg o.d. Placebo
Screening for Resistant Hypertension
compliance
white coat hypertension
hypertension excluded 4 week Single blind placebo run in Treated with A+C+D
Randomisation
*DOT = Directly Observed Therapy
Double blind, Randomised, Placebo-Controlled, Cross-over Study
Home Systolic BP measured at 6 and 12 weeks
Williams B, et al. BMJ Open, 2015 Amiloride Open-Label Run-out 10 -20mg
Plasma Renin
hydrochlorothiazide (HCTZ) on K+ and glucose, but same effect on blood pressure.
in the nephron will be synergistic for Na+ loss and hence BP reduction
– Neutralise the undesired effects of HCTZ, on glucose and K+ – Potentiate the desired effect of HCTZ, on blood pressure
Adjusted means (95% CI) for change from baseline in 2 hr glucose during OGTT. Doses were doubled at 12 weeks. **=p<0.01 vs HCTZ
Difference in change from baseline in OGTT 2 hr glucose for [i] amiloride vs HCTZ, [ii] combination vs HCTZ
2 hr glucose: change from baseline
0.0 0.2 0.4 0.6 0.8 1.0 Baseline 12 weeks 24 weeks
**
Hydrochlorothiazide (HCTZ) 25-50 mg Amiloride 10-20 mg
Amiloride
n=132
Amiloride/HCTZ
n=133
P=0.009
Average difference from HCTZ (mmol/L) (12 & 24 weeks)
Difference in change from baseline in OGTT 2 hr glucose for [i] amiloride vs HCTZ, [ii] combination vs HCTZ
Adjusted means (95% CI) for change from baseline in 2 hr glucose during OGTT. Doses were doubled at 12 weeks. **=p<0.01 vs HCTZ; *=p<0.05 vs HCTZ
2 hr glucose: change from baseline
0.0 0.2 0.4 0.6 0.8 1.0 Baseline 12 weeks 24 weeks
* **
Hydrochlorothiazide (HCTZ) 25-50 mg Amiloride 10-20 mg Amiloride/HCTZ combination 5/12.5 -10/25 mg
High-dose difference from HCTZ (mmol/L) (24 weeks)
Amiloride
n=132
Amiloride/HCTZ
n=133
0.025)
P=0.005 P=0.024
Blood Pressure reduction
Home SBP (mmHg) 125 130 135 140 145 150 Weeks from baseline 12 24 HCTZ Amiloride Combination Home SBP (mmHg) 125 130 135 140 145 150 Weeks from baseline 12 24
HCTZ Amiloride Combination
Home SBP (mean, 95% CI) adjusting for baseline covariates
* p=0.02 for combination vs HCTZ at week 24. Across weeks 12 (low-dose) and 24 (high-dose), BP fall on combination of amiloride and HCTZ was 3·4 (0·9, 5·8) mmHg greater than on HCTZ (p=0·007) 16
Hydrochlorothiazide (HCTZ) 25-50 mg Amiloride 10-20 mg Combination (Amiloride/HCTZ 5/12.5-10/25 mg)
The Prevention And Treatment of
Hypertension Wit ith Algorithm bas based therapY PATHWAY Professor Bryan Williams FESC
Chair of Medicine | University College London
Tom MacDonald FESC, Steve Morant and Morris Brown FESC
Mechanisms for benefit of spironolactone in resistant hypertension in the PATHWAY-2 study
PATHWAY-2 Mechanisms study
Spironolactone 25 – 50mg o.d. Doxazosin MR 4 – 8mg o.d.
Bisoprolol 5 – 10mg o.d. Placebo
Screening for Resistant Hypertension
compliance
white coat hypertension
excluded
4 week Single blind placebo run in Treated with A+C+D
Randomisation
*DOT = Directly Observed Therapy
12 weeks per treatment cycle Forced titration; lower to higher dose at 6 weeks No washout period between cycles Home Systolic BP measured at 6 and 12 weeks
Plasma Renin Aldosterone Aldosterone/ Renin ratio
Haemodynamic studies Haemodynamic studies Haemodynamic studies Haemodynamic studies
Haemodynamic studies Baseline Amiloride Open-Label 12 week Run-out 10 -20mg o.d.
Clinic Systolic BP measured at 6 and 12 weeks
Relationship between renin and aldosterone levels in resistant hypertension
p=0.340 for the linear term p=0.0215 for the quadratic term*
Very few patients with low renin and low aldosterone Many more patients with a relative increase in aldosterone despite a low renin
*Quadratic equation: aldosterone=2.365-0.0309*renin+0.0806*renin*renin
Impact of treatment of resistant hypertension on haemodynamics
*P<0.002
Measurements made at baseline and at the end of each treatment cycle - Cardiodynamics BioZ
Placebo Spironolactone Doxazosin Bisoprolol
*P<0.001
Stroke index Cardiac index
P<0.066 for overall treatment differences
Vascular Resistance index
*P<0.002
Thoracic Fluid index
Effects of amiloride versus spironolactone on clinic systolic BP in resistant hypertension
P<0 . 1
Baseline Placebo Amiloride 10 – 20mg Spironolactone 25 – 50mg Doxazosin 4 – 8mg Bisoprolol 5-10mg
Clinic Blood Pressure (mmHg)
r =0 . 64 p<0 . 1 .
Correlation of BP reduction with amiloride vs spironolactone
Change in clinic systolic BP from baseline on spironolactone Change in clinic systolic BP from baseline on amiloride
Nomura et al. Circ Res. 2017;121:81-88 Reveal Study: DOI: 10.1056/NEJMoa1706444
Objective To determine whether CV morbidity is reduced by better BP control or by choice of diuretic (K+-losing, sparing or neutral) Eligibility Aged > 60, and home SBP > 130 mmHg, and risk factor/marker Sources of patients Registries for acute myocardial ischaemia, PCI, arrhythmia Points of recruitment During acute admission, or via GP Research Database
PATHWAY-2 (Resistant Hypertensive) patients cured by diagnosis/treatment of Conns
B.S. d.o.b. 5/4/1965 Oct 2013 Laparoscopic adrenalectomy 6 mm adenoma Feb 2014 BP 121/88 mmHg Untreated Renin 27 mU/L, aldosterone 143 pmol/L
Aldosterone synthase (CYP11B2)
‘Normal’ CT or MRI scan of adrenals does not exclude Conn’s adenoma CT Overlay
Renin <2.0 mU/L Aldosterone 522 pmol/L
BP 189/114 mmHg Rx: sotalol, irbesartan, doxazosin
(‘FABULAS’)