1. The Prevention And Treatment of Hypertension With Algorithm based therapY
Mechanisms for benefit of spironolactone in resistant hypertension in the PATHWAY-2 study
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

3. Declaration of Interest
None in relation to the content of this work and presentation

4. Background The PATHWAY-2 study hypothesis: PATHWAY-2 Primary Outcome
That resistant hypertension is predominantly a sodium-retaining state
That, further diuretic therapy with spironolactone would be the most effective additional treatment to lower blood pressure
When added to therapy with at least 3 medications; ACE-inhibitor or ARB (A), a CCB (C) and a diuretic (D), i.e. A+C+D.
Williams B, et al. Lancet 2015

5. The PATHWAY-2 Mechanisms study
Pre-specified mechanistic sub-studies, embedded within the PATHWAY-2 study
Key Questions addressed by the PATHWAY-2 Mechanisms study
What is the mechanism for the superior BP-lowering effect of spironolactone in resistant hypertension ?
Would this benefit be replicated by an alternative diuretic, e.g. amiloride, with a similar mechanism of action ?
Can understanding of these mechanisms provide insights into the underlying pathophysiology of resistant hypertension ?

6. PATHWAY-2 Mechanisms study
Doxazosin MR 4 – 8mg o.d.
Randomisation
Screening for Resistant Hypertension
Haemodynamic studies
Treatment A + C + D
DOT* to exclude non- compliance
Home BP to exclude white coat hypertension
Secondary hypertension
excluded
Home Systolic BP measured at
6 and 12 weeks
Spironolactone 25 – 50mg o.d.
Placebo
4 week
Single blind placebo run in Treated with A+C+D
Haemodynamic studies
Haemodynamic
studies
Clinic Systolic BP measured
Baseline
Plasma Renin, Aldosterone, Aldosterone : Renin ratio
at 6 and 12 weeks
*DOT = Directly Observed Therapy
Bisoprolol
5 – 10mg o.d.
Amiloride Open-Label
12 week Run-out
10 -20mg o.d.
Haemodynamic studies
Haemodynamic studies
12 weeks per treatment cycle
Forced titration; lower to higher dose at 6 weeks No washout period between cycles

7. Methodology Objectives
Determine the relationship between baseline renin and aldosterone and the BP response to BP lowering treatments and placebo
Measurement of the impact of treatments on cardiac output, systemic vascular resistance and body fluid volume by impedance cardiography
(Cardiodynamics BioZ, USA)
Determine whether amiloride mg daily is as effective as spironolactone 25-50mg daily at lowering BP in resistant hypertension

8. Study Population Patient Characteristics PATHWAY-2 Mechanisms Study
Main study
Age (years)
60.3yrs (9.7)
61.2yrs (9.6)
Male (%)
72%
69.1%
Baseline clinic BP (mmHg)*
157.9 / 91.1
157.4 / 90.3
eGFR (mls/min/m2)
96.0 (26.2)
91.6 (26.8)
Blood Na+ (mmol/L)
139.7 (3.0)
139.6 (3.0)
Blood K+ (mmol/L)
4.1 (0.4)
24hr Urine Na+ mmol/24hrs
151.0 (73.9)
138 (71.7)
*baseline blood pressure on background treatment with A + C + D

9. Placebo Spironolactone
Impact of baseline Renin, Aldosterone, and Aldosterone/Renin ratio on the BP response to placebo and spironolactone
Placebo
No significant relationships
Similar result for doxazosin and bisoprolol
Spironolactone
Change in home systolic BP mmHg
Renin mass: Aldosterone: Aldo/ Renin:
r , p< r2=0.025, p= r , p=0.0001
Renin (mU/L)
Aldosterone (pmol/L)
Aldosterone / Renin ratio

10. Relationship between renin and aldosterone levels in resistant hypertension
p=0.340 for the linear term p= 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
eGFR: 96mls/min/m2
24hr urinary Na+: 150mmol/24hrs
*Quadratic equation:
aldosterone= *renin *renin*renin

11. Impact of treatment of resistant hypertension on haemodynamics
-7%
*P<0.002
*P<0.001
*P<0.002
P<0.066 for overall treatment differences
Stroke index
Cardiac index
Vascular Resistance index
Thoracic Fluid index
Placebo Spironolactone Doxazosin Bisoprolol
Measurements made at baseline and at the end of each treatment cycle - Cardiodynamics BioZ

12. Effects of amiloride versus spironolactone on clinic systolic BP in resistant hypertension
Correlation of BP reduction with amiloride vs spironolactone
Change in clinic systolic BP from baseline on amiloride
Clinic Blood Pressure (mmHg)
r 0.64=p<
Baseline
Placebo
Amiloride 10 – 20mg
Spironolactone 25 – 50mg
Doxazosin 4 – 8mg
Bisoprolol 5-10mg
Change in clinic systolic BP from baseline on spironolactone

13. Summary and Conclusions
Resistant Hypertension is predominantly a sodium retaining state, characterised by low plasma renin, inappropriately elevated aldosterone, with the most effective treatment associated with a reduction in systemic volume, i.e. a diuretic
Spironolactone (25-50mg daily) appears to act primarily as a diuretic to reduce blood pressure in resistant hypertension
This effect is replicated by amiloride 10-20mg daily
We speculate that a significant proportion of patients with resistant hypertension have inappropriate aldosterone excess due to aldosterone-producing microadenomas that are poorly detected by conventional imaging, explaining the quadratic relationship between aldosterone and renin levels and the superior response to anti- aldosterone diuretic therapy in these patients

14. We thank… Acknowledgements
The Patients who participated in our studies
The Investigators who made it happen
The Funders; the British Heart Foundation and the National Institute for Health Research (NIHR).

15. PATHWAY Executive Committee
PATHWAY Steering Committee
Morris J Brown* | Queen Mary University London
Morris J Brown*
Bryan Williams
Thomas MacDonald
Steve Morant
Ian Ford
Gordon McInnes
Thomas MacDonald | University of Dundee
Peter Sever
David J Webb
Jackie Salsbury
Bryan Williams | University College London
Mark Caulfield Kennedy Cruickshank Isla MacKenzie S Padmanabhan
Steve Morant | Statistician
*Chairman
PATHWAY Study Sites and Local Investigators
Cambridge: A Schumann, J Helmy, C Maniero, TJ Burton, U Quinn, L. Hobbs, J Palmer
Ixworth: J Cannon, S Hood
Birmingham: (2 sites) U Martin, R Hobbs, R Iles Kings College London: K Rutkowski
Dundee: AR McGinnis, JG Houston, E Findlay , C Patterson Leicester: AG Stanley, C White, PS Lacy, P Gupta, SA Nazir, CJ Gardiner-Hill
Exeter: R D’Souza Manchester: H Soran, S Kwok, K Balakrishnan
Edinburgh: V Melville, IM MacIntyre Norwich: K Swe Myint
Glasgow: S Muir, L McCallum St Barts London: D Collier, N Markandu, M Saxena, A Zak, E Enobakhare Imperial College London: J Mackay, SA McG Thom, C Coghlan