Morris J Brown
William Harvey Research InstituteQueen Mary University of London
Research and Trials within the BHS
Topics
• PATHWAYs– Recent (summary of P1, P2, P3)
– Present (mechanisms sub-studies, mainly P2)
– Future (GWAS, Mendelian Randomisation, P4?)
• Studies in Primary Aldosteronism– 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-ordinator
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, KarthiraniBalakrishnan
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 GlasgowSharon Kean, Richard Papworth, Robbie Wilson, Ian FordMonitor: Elizabeth Sprunt
BHF Research Programme
£2.6M award, Nov 2007, to BHS for 3 studies
investigating rational treatment algorithms:
‘PATHWAY’ =
Prevention And Treatment of Hypertension
With Algorithm based therapY
Common theme: Should renin
measurement be routine in hypertension?
Summary of Questions
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?
Combination versus sequential monotherapy for initial treatment of hypertension (PATHWAY-1)
N=605
Results: Home SBP
Unadjusted mean home SBP (95% CI) at each visit
Ho
me
sys
tolic
BP
(m
mH
g)
120
125
130
135
140
145
150
155
Weeks from baseline
0 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
0
20
40
60
80
100
Phase 1 Phase 2 Phase 3
%
Controlled BPHBP< 135/85mmHg or Clinic BP <
140/90mmHg
Combination MonoRx
Proof of AB/CD But combination trumps personalisation:
‘initial combination trumps initialledmonotherapy’
Hom
e sy
stol
ic B
P (m
mH
g)
125
130
135
140
145
150
Renin tertile
Bottom Middle Top
HCTZ
Losartan
Combination
Randomised initial treatment
Combination HCTZ Losartan
Difference (95%
CI) p-value
Difference (95% CI)
p-value Difference (95%
CI) p-value
Top vs Bottom renin tertile(1) -1·41 (-3·52,0·71) 0·193 4·31 (-2·26,6·35) <·001 -3·71 (-5·70,-1·71) <·001
Aged over 55 vs 55 and under(1)
1·45 (-0·29, 3·19) 0·103 -2·94 (-4·73,-1·15) 0·001 -1·89 (-3·62,-0·16) 0·032
Renin (per 10 fold increase) -1·80 (-4·75,1·16) 0·235 4·96 (2·12,7·80) <·001 -3·70 (-6·43,-0·97) 0·008
Age (per 10 years) 0·13 (-0·85,1·12) 0·787 -0·97 (-1·98,0·04) 0·062 -0·20 (-1·18,0·77) 0·682
Baseline HSBP 0·29 (0·22,0·36) <·001 0·48 (0·42,0·54) <·001 0·55 (0·48,0·61) <·001
Never vs previously treated 1·83 (-0·41,4·08) 0·111 -3·01 (-5·26,-0·77) 0·009 -2·85 (-4·96,-0·73) 0·009
Randomised initial treatment
Combination HCTZ Losartan
Difference (95%
CI) p-value
Difference (95% CI)
p-value Difference (95%
CI) p-value
Top vs Bottom renin tertile(1) -1·41 (-3·52,0·71) 0·193 4·31 (-2·26,6·35) <·001 -3·71 (-5·70,-1·71) <·001
Aged over 55 vs 55 and under(1)
1·45 (-0·29, 3·19) 0·103 -2·94 (-4·73,-1·15) 0·001 -1·89 (-3·62,-0·16) 0·032
Renin (per 10 fold increase) -1·80 (-4·75,1·16) 0·235 4·96 (2·12,7·80) <·001 -3·70 (-6·43,-0·97) 0·008
Age (per 10 years) 0·13 (-0·85,1·12) 0·787 -0·97 (-1·98,0·04) 0·062 -0·20 (-1·18,0·77) 0·682
Baseline HSBP 0·29 (0·22,0·36) <·001 0·48 (0·42,0·54) <·001 0·55 (0·48,0·61) <·001
Never vs previously treated 1·83 (-0·41,4·08) 0·111 -3·01 (-5·26,-0·77) 0·009 -2·85 (-4·96,-0·73) 0·009
PATHWAY-2 Study of Resistant Hypertension
Spironolactone25 – 50mg o.d.
Doxazosin MR4 – 8mg o.d.
Bisoprolol5 – 10mg o.d.
Placebo
Screening forResistant Hypertension• Rx A + C + D• DOT* to exclude non-
compliance• Home BP to exclude
white coat hypertension
• Secondary hypertension excluded
4 weekSingle blind placebo run in
Treated with A+C+D
Randomisation
*DOT = Directly Observed Therapy
Double blind, Randomised, Placebo-Controlled, Cross-over Study
• 12 weeks per treatment cycle• Forced titration; lower to higher dose at 6 weeks• No washout period between cycles
Home Systolic BP
measured at6 and 12 weeks
Williams B, et al. BMJ Open, 2015
AmilorideOpen-Label
Run-out10 -20mg
o.d.
Plasma Renin
Primary Outcome
PATHWAY-3 study of amiloride vs HCTZ
• Amiloride will have the opposite effect to hydrochlorothiazide (HCTZ) on K+ and glucose, but same effect on blood pressure.
• Combination of diuretics with different sites of action in the nephron will be synergistic for Na+ loss and hence BP reduction
• Consequently, the combination of half-maximal doses of amiloride and HCTZ will:
– 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
Hierarchical primary endpointsDifference in change from baseline in OGTT 2 hr glucose
for [i] amiloride vs HCTZ, [ii] combination vs HCTZ
2 h
r g
lucose:
ch
an
ge f
rom
baselin
e
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
Baseline 12 weeks 24 weeks
**
Hydrochlorothiazide (HCTZ) 25-50 mgAmiloride 10-20 mg
Amiloriden=132
Amiloride/HCTZ n=133
-0.55 (-0.96,-0.14)
P=0.009
Average difference from HCTZ (mmol/L) (12 & 24 weeks)
Hierarchical primary endpointsDifference 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 h
r g
lucose:
ch
an
ge f
rom
baselin
e
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
Baseline 12 weeks 24 weeks
***
Hydrochlorothiazide (HCTZ) 25-50 mgAmiloride 10-20 mgAmiloride/HCTZ combination 5/12.5 -10/25 mg
High-dose difference from HCTZ (mmol/L) (24 weeks)
Amiloriden=132
Amiloride/HCTZ n=133
-0.73 (-1.20,-0.25)-0.50 (-0.98, -
0.025)
P=0.005 P=0.024
Secondary endpointsBlood Pressure reduction
Hom
e S
BP
(m
mH
g)
125
130
135
140
145
150
Weeks from baseline
0 12 24
HCTZAmilorideCombination
Hom
e S
BP
(m
mH
g)
125
130
135
140
145
150
Weeks from baseline
0 12 24
*
HCTZAmilorideCombination
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)
n-f
old
in
cre
ase in
ren
in
1
2
4
8
16
Weeks from baseline
0 12 24
***
Hydrochlorothiazide (HCTZ) 25-50 mg
Amiloride 10-20 mg
Combination (Amiloride/HCTZ 5/12.5-10/25 mg)
The Prevention And Treatment of Hypertension With Algorithm based therapYPATHWAY
Professor Bryan Williams FESC Chair of Medicine | University College London
Tom MacDonald FESC, Steve Morant and Morris Brown FESC
on behalf of the PATHWAY Investigators
Mechanisms for benefit of spironolactone in resistant hypertension in the PATHWAY-2 study
PATHWAY-2 Mechanisms study
Spironolactone25 – 50mg o.d.
Doxazosin MR4 – 8mg o.d.
Bisoprolol5 – 10mg o.d.
Placebo
Screening forResistant Hypertension
• Treatment A + C + D• DOT* to exclude non-
compliance• Home BP to exclude
white coat hypertension• Secondary hypertension
excluded
4 weekSingle blind placebo run in
Treated with A+C+D
Randomisation
*DOT = Directly Observed Therapy
12 weeks per treatment cycleForced titration; lower to higher dose at 6 weeks
No washout period between cycles
Home Systolic BP measured at
6 and 12 weeks
Plasma ReninAldosteroneAldosterone/
Renin ratio
Haemodynamicstudies
Haemodynamicstudies
Haemodynamicstudies
Haemodynamicstudies
Haemodynamicstudies
Baseline
AmilorideOpen-Label
12 week Run-out10 -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 increasein 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<0.001
Baseline Placebo Amiloride10 – 20mg
Spironolactone25 – 50mg
Doxazosin4 – 8mg
Bisoprolol5-10mg
Clin
ic B
loo
d P
ress
ure
(m
mH
g)
r =0.64 p<0.0001.
Correlation of BP reduction with amiloride vs spironolactone
Change in clinic systolic BP from baseline on spironolactone
Ch
ange
in c
linic
sys
tolic
BP
fro
m b
asel
ine
on
am
ilori
de
Nomura et al. Circ Res. 2017;121:81-88 Reveal Study: DOI: 10.1056/NEJMoa1706444
Mendelian randomisation predicts morbidity-mortality outcomes
ObjectiveTo determine whether CV morbidity is reduced by better BP control or by choice of diuretic (K+-losing, sparing or neutral)
EligibilityAged > 60, and home SBP > 130 mmHg, and risk factor/markerSources of patientsRegistries for acute myocardial ischaemia, PCI, arrhythmiaPoints of recruitmentDuring acute admission, or via GP Research Database
Nutshell summary of PATHWAY-4
Is Metomidate PET CT superior to Adrenal venous sampling in predicting ouTCome from adrenalectomy in patients with primary Hyperaldosteronism (MATCH): a multi -centre, randomised, within-patient comparison of diagnostic techniques
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
Topics
•PATHWAYs• Recent (summary of P1, P2, P3)
• Present (mechanisms sub-studies, mainly P2)
• Future (GWAS, Mendelian Randomisation, P4?)
•Studies in Primary Aldosteronism• 11C-metomidate PET CT vs Adrenal Vein Sampling (‘MATCH’)
• Endoscopic radiofrequency ablation of adrenal adenomas(‘FABULAS’)