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, 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 PATHWAY Executive Committee Morris J Brown – Gordon McInnes, Morris J Brown (Chairman): University of Cambridge Chairman Thomas MacDonald Peter Sever Thomas MacDonald: University of Dundee Bryan Williams Isla MacKenzie Bryan Williams: University College London David J Webb Sandosh Padmanabhan Data Centre and Monitor Mark Caulfield Jackie Salsbury – Co- ordinator Robertson Centre for Biostatistics, University of Glasgow Sharon Kean, Richard Papworth, Robbie Wilson, Ian Ford J Kennedy Cruickshank Steve Morant - Statistician Monitor: Elizabeth Sprunt Ian Ford PATHWAY Study Sites and Investigators Cambridge: Anne Schumann, Jo Helmy, Carmela Maniero, Timothy J Ixworth: John Cannon, Sue Hood Burton, Ursula Quinn, Lorraine Hobbs, Jo Palmer, Birmingham: (2 sites) Una Martin, Richard Hobbs, Rachel Iles Kings College London: Krzysztof Rutkowski Dundee: Alison R McGinnis, JG Houston, Evekyn Findlay , Caroline Imperial College London: Judith Mackay, Simon A Patterson, McG Thom, Candida Coghlan Leicester: Adrian G Stanley, Christobelle White, Peter Lacy, Pankaj Manchester: Handrean Soran, See Kwok, Karthirani Gupta, Sheraz A Nazir, Caroline J. Gardiner-Hill Balakrishnan Edinburgh: Vanessa Melville, Iain M MacIntyre Norwich: Khin Swe Myint, Judith Gowlett St Barts London: David Collier, Nirmala Markandu, Manish Saxena, Glasgow: Scott Muir, Linsay McCallum Anne Zak, Enamuna Enobakhare
BHF Research Programme £2.6M award, Nov 2007, to BHS for 3 studies investigating rational treatment algorithms: ‘PATHWAY’ = P revention A nd T reatment of H ypertension W ith A lgorithm based therap Y 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?
Com ombination ver ersus seq sequential mon onotherap apy for or in initial tr treatment of of hyp ypertension (P (PATHWAY-1) N=605
Result lts: Home SBP 155 8mmHg 2.9mmHg 150 Combination therapy 145 Monotherapy, HCTZ first Monotherapy, losartan first Home systolic BP (mmHg) 140 +1.2mmHg 135 p=0.13 130 4.9mmHg p < 0.001 125 Phase 1 Phase 2 Phase 3 120 0 4 8 12 16 24 32 38 44 52 Weeks from baseline
Controlled BP HBP< 135/85mmHg or Clinic BP < 140/90mmHg 100 80 60 % 40 20 0 Phase 1 Phase 2 Phase 3 Combination MonoRx
Proof of f AB/CD But combination tru trumps personalisation: ‘ initial combination trumps initialled monotherapy’ 150 145 HCTZ Home systolic BP (mmHg) 140 Losartan 135 Randomised initial treatment 130 HCTZ Losartan Combination Difference (95% Difference (95% lue p-value p-value CI) CI) 125 Bottom Middle Top Top vs Bottom renin tertile (1) 4·31 (-2·26,6·35) <·001 -3·71 (-5·70,-1·71) <·001 Renin tertile Aged over 55 vs 55 and -2·94 (-4·73,-1·15) 0·001 -1·89 (-3·62,-0·16) 0·032 under (1) Renin (per 10 fold increase) 4·96 (2·12,7·80) <·001 -3·70 (-6·43,-0·97) 0·008
PATHWAY-2 Study of Resistant Hypertension Double blind, Randomised, Placebo-Controlled, Cross-over Study Doxazosin MR 4 – 8mg o.d. Randomisation Screening for Resistant Hypertension • Rx A + C + D • DOT* to exclude non- Home Systolic compliance Spironolactone Placebo • BP Home BP to exclude 25 – 50mg o.d. 4 week white coat measured at Single blind placebo run in hypertension 6 and 12 weeks Treated with A+C+D • Secondary hypertension excluded Amiloride Open-Label Plasma Run-out Renin Bisoprolol *DOT = Directly Observed Therapy 10 -20mg 5 – 10mg o.d. o.d. • 12 weeks per treatment cycle • Forced titration; lower to higher dose at 6 weeks • No washout period between cycles Williams B, et al. BMJ Open, 2015
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
Hierarchical primary endpoints Difference in change from baseline in OGTT 2 hr glucose for [i] amiloride vs HCTZ, [ii] combination vs HCTZ 1.0 Hydrochlorothiazide (HCTZ) 25-50 mg Amiloride 10-20 mg 0.8 2 hr glucose: change from baseline 0.6 0.4 0.2 Average difference from HCTZ (mmol/L) (12 & 24 weeks) 0.0 Amiloride Amiloride/HCTZ -0.2 n=132 n=133 -0.4 ** -0.6 -0.55 (-0.96,-0.14) -0.8 P=0.009 -1.0 Baseline 12 weeks 24 weeks 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 endpoints Difference in change from baseline in OGTT 2 hr glucose for [i] amiloride vs HCTZ, [ii] combination vs HCTZ 1.0 Hydrochlorothiazide (HCTZ) 25-50 mg Amiloride 10-20 mg 0.8 Amiloride/HCTZ combination 5/12.5 -10/25 mg 2 hr glucose: change from baseline 0.6 0.4 High-dose difference from HCTZ 0.2 (mmol/L) (24 weeks) 0.0 Amiloride Amiloride/HCTZ -0.2 * n=132 n=133 -0.4 ** -0.50 (-0.98, - -0.6 -0.73 (-1.20,-0.25) 0.025) -0.8 P=0.005 P=0.024 -1.0 Baseline 12 weeks 24 weeks 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
Secondary endpoints Blood Pressure reduction 150 150 HCTZ HCTZ Amiloride Amiloride Combination Combination 145 145 Home SBP (mmHg) Home SBP (mmHg) 140 140 Home SBP (mean, 95% CI) adjusting for 135 135 baseline covariates * * p=0.02 for combination vs HCTZ at week 24. 130 130 Across weeks 12 (low-dose) and 24 (high-dose), BP Hydrochlorothiazide (HCTZ) 25-50 mg 16 fall on combination of amiloride and HCTZ was 3·4 Amiloride 10-20 mg Combination (Amiloride/HCTZ 5/12.5-10/25 mg) (0·9, 5·8) mmHg greater than on HCTZ (p=0·007) 125 125 0 0 12 12 24 24 Weeks from baseline Weeks from baseline
The Prevention And Treatment of of Hy Hypertension Wit ith Algorithm bas based therapY PATHWAY 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
PATHWAY-2 Mechanisms study Doxazosin MR 4 – 8mg o.d. Randomisation Haemodynamic Screening for studies Resistant Hypertension • Treatment A + C + D Home Systolic BP • DOT* to exclude non- Spironolactone measured at Placebo compliance 25 – 50mg o.d. 6 and 12 weeks 4 week • Home BP to exclude Single blind placebo run in Haemodynamic white coat hypertension Haemodynamic studies Treated with A+C+D studies • Secondary hypertension excluded Clinic Systolic BP measured Baseline at 6 and 12 weeks Plasma Renin Bisoprolol *DOT = Directly Observed Therapy Amiloride Aldosterone 5 – 10mg o.d. Open-Label Aldosterone/ 12 week Run-out Haemodynamic Renin ratio studies 10 -20mg o.d. Haemodynamic studies 12 weeks per treatment cycle Forced titration; lower to higher dose at 6 weeks No washout period between cycles
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 * P<0.001 *P<0.002 P<0.066 for overall treatment differences Cardiac index Stroke index Vascular Resistance index Thoracic Fluid index Spironolactone Doxazosin Placebo Bisoprolol Measurements made at baseline and at the end of each treatment cycle - Cardiodynamics BioZ
Effects of amiloride versus spironolactone on clinic systolic BP in resistant hypertension P <0 . 0 0 1 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 <0 . 0 0 0 1 . Baseline Placebo Amiloride Spironolactone Doxazosin Bisoprolol Change in clinic systolic BP from baseline on spironolactone 10 – 20mg 25 – 50mg 4 – 8mg 5-10mg
Mendelian randomisation predicts morbidity-mortality outcomes Nomura et al. Circ Res . 2017;121:81-88 Reveal Study: DOI: 10.1056/NEJMoa1706444
Recommend
More recommend
