Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies

In the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension. PATHWAY-2 was a randomised...

Celý popis

Uložené v:

Podrobná bibliografia
Vydané v:	The lancet. Diabetes & endocrinology Ročník 6; číslo 6; s. 464
Hlavní autori:	Williams, Bryan, MacDonald, Thomas M, Morant, Steve V, Webb, David J, Sever, Peter, McInnes, Gordon T, Ford, Ian, Cruickshank, J Kennedy, Caulfield, Mark J, Padmanabhan, Sandosh, Mackenzie, Isla S, Salsbury, Jackie, Brown, Morris J
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	England 01.06.2018
Predmet:	Aldosterone - metabolism Amiloride - therapeutic use Antihypertensive Agents - therapeutic use Bisoprolol - therapeutic use Blood Pressure - drug effects Doxazosin - therapeutic use Female Hemodynamics - drug effects Humans Hypertension - drug therapy Male Middle Aged Randomized Controlled Trials as Topic Spironolactone - therapeutic use
ISSN:	2213-8595, 2213-8595
On-line prístup:	Zistit podrobnosti o prístupe
Tagy:	Pridať tag Žiadne tagy, Buďte prvý, kto otaguje tento záznam!

Abstract	In the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension. PATHWAY-2 was a randomised, double-blind crossover trial done at 14 UK primary and secondary care sites in 314 patients with resistant hypertension. Patients were given 12 weeks of once daily treatment with each of placebo, spironolactone 25-50 mg, bisoprolol 5-10 mg, and doxazosin 4-8 mg and the change in home systolic blood pressure was assessed as the primary outcome. In our three substudies, we assessed plasma aldosterone, renin, and aldosterone-to-renin ratio (ARR) as predictors of home systolic blood pressure, and estimated prevalence of primary aldosteronism (substudy 1); assessed the effects of each drug in terms of thoracic fluid index, cardiac index, stroke index, and systemic vascular resistance at seven sites with haemodynamic monitoring facilities (substudy 2); and assessed the effect of amiloride 10-20 mg once daily on clinic systolic blood pressure during an optional 6-12 week open-label runout phase (substudy 3). The PATHWAY-2 trial is registered with EudraCT, number 2008-007149-30, and ClinicalTrials.gov, number NCT02369081. Of the 314 patients in PATHWAY-2, 269 participated in one or more of the three substudies: 126 in substudy 1, 226 in substudy 2, and 146 in substudy 3. Home systolic blood pressure reduction by spironolactone was predicted by ARR (r =0·13, p<0·0001) and plasma renin (r =0·11, p=0·00024). 42 patients had low renin concentrations (predefined as the lowest tertile of plasma renin), of which 31 had a plasma aldosterone concentration greater than the mean value for all 126 patients (250 pmol/L). Thus, 31 (25% [95% CI 17-33]) of 126 patients were deemed to have inappropriately high aldosterone concentrations. Thoracic fluid content was reduced by 6·8% from baseline (95% CI 4·0 to 8·8; p<0·0001) with spironolactone, but not other treatments. Amiloride (10 mg once daily) reduced clinic systolic blood pressure by 20·4 mm Hg (95% CI 18·3-22·5), compared with a reduction of 18·3 mm Hg (16·2-20·5) with spironolactone (25 mg once daily). No serious adverse events were recorded, and adverse symptoms were not systematically recorded after the end of the double-blind treatment. Mean plasma potassium concentrations increased from 4·02 mmol/L (95% CI 3·95-4·08) on placebo to 4·50 (4·44-4·57) on amiloride (p<0·0001). Our results suggest that resistant hypertension is commonly a salt-retaining state, most likely due to inappropriate aldosterone secretion. Mineralocorticoid receptor blockade by spironolactone overcomes the salt retention and resistance of hypertension to treatment. Amiloride seems to be as effective an antihypertensive as spironolactone, offering a substitute treatment for resistant hypertension. British Heart Foundation and UK National Institute for Health Research.
AbstractList	In the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension. PATHWAY-2 was a randomised, double-blind crossover trial done at 14 UK primary and secondary care sites in 314 patients with resistant hypertension. Patients were given 12 weeks of once daily treatment with each of placebo, spironolactone 25-50 mg, bisoprolol 5-10 mg, and doxazosin 4-8 mg and the change in home systolic blood pressure was assessed as the primary outcome. In our three substudies, we assessed plasma aldosterone, renin, and aldosterone-to-renin ratio (ARR) as predictors of home systolic blood pressure, and estimated prevalence of primary aldosteronism (substudy 1); assessed the effects of each drug in terms of thoracic fluid index, cardiac index, stroke index, and systemic vascular resistance at seven sites with haemodynamic monitoring facilities (substudy 2); and assessed the effect of amiloride 10-20 mg once daily on clinic systolic blood pressure during an optional 6-12 week open-label runout phase (substudy 3). The PATHWAY-2 trial is registered with EudraCT, number 2008-007149-30, and ClinicalTrials.gov, number NCT02369081. Of the 314 patients in PATHWAY-2, 269 participated in one or more of the three substudies: 126 in substudy 1, 226 in substudy 2, and 146 in substudy 3. Home systolic blood pressure reduction by spironolactone was predicted by ARR (r =0·13, p<0·0001) and plasma renin (r =0·11, p=0·00024). 42 patients had low renin concentrations (predefined as the lowest tertile of plasma renin), of which 31 had a plasma aldosterone concentration greater than the mean value for all 126 patients (250 pmol/L). Thus, 31 (25% [95% CI 17-33]) of 126 patients were deemed to have inappropriately high aldosterone concentrations. Thoracic fluid content was reduced by 6·8% from baseline (95% CI 4·0 to 8·8; p<0·0001) with spironolactone, but not other treatments. Amiloride (10 mg once daily) reduced clinic systolic blood pressure by 20·4 mm Hg (95% CI 18·3-22·5), compared with a reduction of 18·3 mm Hg (16·2-20·5) with spironolactone (25 mg once daily). No serious adverse events were recorded, and adverse symptoms were not systematically recorded after the end of the double-blind treatment. Mean plasma potassium concentrations increased from 4·02 mmol/L (95% CI 3·95-4·08) on placebo to 4·50 (4·44-4·57) on amiloride (p<0·0001). Our results suggest that resistant hypertension is commonly a salt-retaining state, most likely due to inappropriate aldosterone secretion. Mineralocorticoid receptor blockade by spironolactone overcomes the salt retention and resistance of hypertension to treatment. Amiloride seems to be as effective an antihypertensive as spironolactone, offering a substitute treatment for resistant hypertension. British Heart Foundation and UK National Institute for Health Research. In the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension.BACKGROUNDIn the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension.PATHWAY-2 was a randomised, double-blind crossover trial done at 14 UK primary and secondary care sites in 314 patients with resistant hypertension. Patients were given 12 weeks of once daily treatment with each of placebo, spironolactone 25-50 mg, bisoprolol 5-10 mg, and doxazosin 4-8 mg and the change in home systolic blood pressure was assessed as the primary outcome. In our three substudies, we assessed plasma aldosterone, renin, and aldosterone-to-renin ratio (ARR) as predictors of home systolic blood pressure, and estimated prevalence of primary aldosteronism (substudy 1); assessed the effects of each drug in terms of thoracic fluid index, cardiac index, stroke index, and systemic vascular resistance at seven sites with haemodynamic monitoring facilities (substudy 2); and assessed the effect of amiloride 10-20 mg once daily on clinic systolic blood pressure during an optional 6-12 week open-label runout phase (substudy 3). The PATHWAY-2 trial is registered with EudraCT, number 2008-007149-30, and ClinicalTrials.gov, number NCT02369081.METHODSPATHWAY-2 was a randomised, double-blind crossover trial done at 14 UK primary and secondary care sites in 314 patients with resistant hypertension. Patients were given 12 weeks of once daily treatment with each of placebo, spironolactone 25-50 mg, bisoprolol 5-10 mg, and doxazosin 4-8 mg and the change in home systolic blood pressure was assessed as the primary outcome. In our three substudies, we assessed plasma aldosterone, renin, and aldosterone-to-renin ratio (ARR) as predictors of home systolic blood pressure, and estimated prevalence of primary aldosteronism (substudy 1); assessed the effects of each drug in terms of thoracic fluid index, cardiac index, stroke index, and systemic vascular resistance at seven sites with haemodynamic monitoring facilities (substudy 2); and assessed the effect of amiloride 10-20 mg once daily on clinic systolic blood pressure during an optional 6-12 week open-label runout phase (substudy 3). The PATHWAY-2 trial is registered with EudraCT, number 2008-007149-30, and ClinicalTrials.gov, number NCT02369081.Of the 314 patients in PATHWAY-2, 269 participated in one or more of the three substudies: 126 in substudy 1, 226 in substudy 2, and 146 in substudy 3. Home systolic blood pressure reduction by spironolactone was predicted by ARR (r2=0·13, p<0·0001) and plasma renin (r2=0·11, p=0·00024). 42 patients had low renin concentrations (predefined as the lowest tertile of plasma renin), of which 31 had a plasma aldosterone concentration greater than the mean value for all 126 patients (250 pmol/L). Thus, 31 (25% [95% CI 17-33]) of 126 patients were deemed to have inappropriately high aldosterone concentrations. Thoracic fluid content was reduced by 6·8% from baseline (95% CI 4·0 to 8·8; p<0·0001) with spironolactone, but not other treatments. Amiloride (10 mg once daily) reduced clinic systolic blood pressure by 20·4 mm Hg (95% CI 18·3-22·5), compared with a reduction of 18·3 mm Hg (16·2-20·5) with spironolactone (25 mg once daily). No serious adverse events were recorded, and adverse symptoms were not systematically recorded after the end of the double-blind treatment. Mean plasma potassium concentrations increased from 4·02 mmol/L (95% CI 3·95-4·08) on placebo to 4·50 (4·44-4·57) on amiloride (p<0·0001).FINDINGSOf the 314 patients in PATHWAY-2, 269 participated in one or more of the three substudies: 126 in substudy 1, 226 in substudy 2, and 146 in substudy 3. Home systolic blood pressure reduction by spironolactone was predicted by ARR (r2=0·13, p<0·0001) and plasma renin (r2=0·11, p=0·00024). 42 patients had low renin concentrations (predefined as the lowest tertile of plasma renin), of which 31 had a plasma aldosterone concentration greater than the mean value for all 126 patients (250 pmol/L). Thus, 31 (25% [95% CI 17-33]) of 126 patients were deemed to have inappropriately high aldosterone concentrations. Thoracic fluid content was reduced by 6·8% from baseline (95% CI 4·0 to 8·8; p<0·0001) with spironolactone, but not other treatments. Amiloride (10 mg once daily) reduced clinic systolic blood pressure by 20·4 mm Hg (95% CI 18·3-22·5), compared with a reduction of 18·3 mm Hg (16·2-20·5) with spironolactone (25 mg once daily). No serious adverse events were recorded, and adverse symptoms were not systematically recorded after the end of the double-blind treatment. Mean plasma potassium concentrations increased from 4·02 mmol/L (95% CI 3·95-4·08) on placebo to 4·50 (4·44-4·57) on amiloride (p<0·0001).Our results suggest that resistant hypertension is commonly a salt-retaining state, most likely due to inappropriate aldosterone secretion. Mineralocorticoid receptor blockade by spironolactone overcomes the salt retention and resistance of hypertension to treatment. Amiloride seems to be as effective an antihypertensive as spironolactone, offering a substitute treatment for resistant hypertension.INTERPRETATIONOur results suggest that resistant hypertension is commonly a salt-retaining state, most likely due to inappropriate aldosterone secretion. Mineralocorticoid receptor blockade by spironolactone overcomes the salt retention and resistance of hypertension to treatment. Amiloride seems to be as effective an antihypertensive as spironolactone, offering a substitute treatment for resistant hypertension.British Heart Foundation and UK National Institute for Health Research.FUNDINGBritish Heart Foundation and UK National Institute for Health Research.
Author	Cruickshank, J Kennedy Williams, Bryan MacDonald, Thomas M Salsbury, Jackie Sever, Peter Webb, David J McInnes, Gordon T Caulfield, Mark J Mackenzie, Isla S Ford, Ian Brown, Morris J Morant, Steve V Padmanabhan, Sandosh
Author_xml	– sequence: 1 givenname: Bryan surname: Williams fullname: Williams, Bryan organization: UCL Institute of Cardiovascular Sciences, University College London, London, UK; National Institute for Health Research, UCL Hospitals Biomedical Research Centre, London, UK – sequence: 2 givenname: Thomas M surname: MacDonald fullname: MacDonald, Thomas M organization: Medicines Monitoring Unit, Molecular and Clinical Medicine, University of Dundee, Dundee, UK – sequence: 3 givenname: Steve V surname: Morant fullname: Morant, Steve V organization: Medicines Monitoring Unit, Molecular and Clinical Medicine, University of Dundee, Dundee, UK – sequence: 4 givenname: David J surname: Webb fullname: Webb, David J organization: Clinical Pharmacology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK – sequence: 5 givenname: Peter surname: Sever fullname: Sever, Peter organization: Centre of Circulatory Health, Imperial College London, London, UK – sequence: 6 givenname: Gordon T surname: McInnes fullname: McInnes, Gordon T organization: BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK – sequence: 7 givenname: Ian surname: Ford fullname: Ford, Ian organization: Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK – sequence: 8 givenname: J Kennedy surname: Cruickshank fullname: Cruickshank, J Kennedy organization: Department of Nutritional Sciences, King's College London, London, UK – sequence: 9 givenname: Mark J surname: Caulfield fullname: Caulfield, Mark J organization: William Harvey Research Institute, Queen Mary University of London, London, UK; NIHR Barts Hospital Biomedical Research Centre, London, UK – sequence: 10 givenname: Sandosh surname: Padmanabhan fullname: Padmanabhan, Sandosh organization: BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK – sequence: 11 givenname: Isla S surname: Mackenzie fullname: Mackenzie, Isla S organization: Medicines Monitoring Unit, Molecular and Clinical Medicine, University of Dundee, Dundee, UK – sequence: 12 givenname: Jackie surname: Salsbury fullname: Salsbury, Jackie organization: William Harvey Research Institute, Queen Mary University of London, London, UK; NIHR Barts Hospital Biomedical Research Centre, London, UK – sequence: 13 givenname: Morris J surname: Brown fullname: Brown, Morris J email: morris.brown@qmul.ac.uk organization: William Harvey Research Institute, Queen Mary University of London, London, UK; NIHR Barts Hospital Biomedical Research Centre, London, UK. Electronic address: morris.brown@qmul.ac.uk
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/29655877$$D View this record in MEDLINE/PubMed
BookMark	eNpNkN1KxDAQhYMo_j-CkksFq0m6aRrvFvEPBAUV8WpJ0lk30iY1k17sy_isVl3BqxmG75zhnB2yHmIAQg44O-WMV2ePQvCyqGWtjnh9XDKmeFGvke3VWcv1f_sW2Ud8Z4xxJsuqZptkS-hKjmK1TT4vQxNd8gGoCQ1dGOhiswym8466hQlvgNQHmgA9ZhMyXSx7SBkC-hhOfjS2jbGh_YjgkOAb7WPAUZcjxd6nGGJrXB4T0Jjo6NzG5Bs4p3kB9GH6dPMyfS0E7eD7n8cOKQ4W89B4wD2yMTctwv5q7pLnq8uni5vi7v769mJ6V7gxRi4sg0nlSmeF5JqVUtS25EY32iknhBNzqMqJk6BMqRlYXpu5ngvLtVFSTYwVu-To17dP8WMAzLPOo4O2NQHigDPBhKxZpZQe0cMVOtgOmlmffGfScvbXqfgCbux_5Q
CitedBy_id	crossref_primary_10_1016_j_lpm_2019_07_027 crossref_primary_10_1161_HYPERTENSIONAHA_125_24793 crossref_primary_10_1210_er_2018_00139 crossref_primary_10_1080_17512433_2020_1766964 crossref_primary_10_1161_CIRCRESAHA_121_318083 crossref_primary_10_1161_HYPERTENSIONAHA_120_15026 crossref_primary_10_1016_j_preghy_2021_06_005 crossref_primary_10_1161_CIR_0000000000001356 crossref_primary_10_1161_CIRCULATIONAHA_123_064318 crossref_primary_10_1177_17151635251343907 crossref_primary_10_1210_clinem_dgae145 crossref_primary_10_1007_s11906_023_01253_5 crossref_primary_10_1002_j_2040_4603_2023_tb00256_x crossref_primary_10_1007_s12020_025_04322_8 crossref_primary_10_3390_pharmaceutics13050714 crossref_primary_10_1093_ajh_hpaf156 crossref_primary_10_1038_s41440_020_0428_y crossref_primary_10_1111_jch_14742 crossref_primary_10_1161_HYPERTENSIONAHA_125_24711 crossref_primary_10_15829_1560_4071_2024_6117 crossref_primary_10_1111_jch_14740 crossref_primary_10_1161_CIRCULATIONAHA_121_055329 crossref_primary_10_1038_s41569_025_01131_4 crossref_primary_10_1093_ehjcvp_pvae049 crossref_primary_10_1001_jama_2023_17087 crossref_primary_10_1210_clinem_dgz315 crossref_primary_10_7326_M20_3798 crossref_primary_10_1093_eurheartj_ehac299 crossref_primary_10_1093_eurheartj_ehab484 crossref_primary_10_18087_cardio_2019_12_n547 crossref_primary_10_1016_S0140_6736_19_32135_X crossref_primary_10_1007_s11886_019_1209_6 crossref_primary_10_1002_pdi_2389 crossref_primary_10_3389_fmed_2021_653634 crossref_primary_10_1038_s41371_020_0336_2 crossref_primary_10_1177_1753495X19825967 crossref_primary_10_1161_JAHA_120_018827 crossref_primary_10_1097_HJH_0000000000003480 crossref_primary_10_1038_s41440_024_01843_z crossref_primary_10_1097_HJH_0000000000003240 crossref_primary_10_1097_HJH_0000000000004054 crossref_primary_10_1210_jc_2018_01197 crossref_primary_10_1055_a_2645_8838 crossref_primary_10_1161_HYPERTENSIONAHA_118_11064 crossref_primary_10_3390_ijms23094803 crossref_primary_10_1007_s40119_020_00203_5 crossref_primary_10_1016_S2213_8587_18_30080_9 crossref_primary_10_1097_HJH_0000000000002453 crossref_primary_10_1016_j_coemr_2019_07_001 crossref_primary_10_12688_f1000research_21669_1 crossref_primary_10_1016_j_pcad_2020_08_001 crossref_primary_10_1093_eurheartj_ehy339 crossref_primary_10_1097_HJH_0000000000002611 crossref_primary_10_1146_annurev_med_050922_052605 crossref_primary_10_1007_s15027_024_3715_8 crossref_primary_10_1161_HYP_0000000000000249 crossref_primary_10_1161_HYPERTENSIONAHA_123_21287 crossref_primary_10_1016_j_nefro_2025_501399 crossref_primary_10_1093_cvr_cvad165 crossref_primary_10_3390_jcm11051455 crossref_primary_10_7759_cureus_36184 crossref_primary_10_1007_s13410_022_01143_7 crossref_primary_10_1007_s11906_019_0924_0 crossref_primary_10_1111_jch_14042 crossref_primary_10_1093_ajh_hpad032 crossref_primary_10_1080_14779072_2024_2401875 crossref_primary_10_1093_ajh_hpae003 crossref_primary_10_1159_000515809 crossref_primary_10_1210_clinem_dgad071 crossref_primary_10_1016_j_ajpc_2020_100001 crossref_primary_10_1177_17151635251352537 crossref_primary_10_7326_AITC201905070 crossref_primary_10_3390_nu13030875 crossref_primary_10_52485_19986173_2025_2_49 crossref_primary_10_1007_s11886_023_01966_8 crossref_primary_10_1093_eurheartj_ehae938 crossref_primary_10_3389_fphys_2022_1001434 crossref_primary_10_1056_NEJMc2302673 crossref_primary_10_1038_s41440_023_01204_2 crossref_primary_10_1093_eurheartj_ehaf225 crossref_primary_10_1161_CIRCULATIONAHA_121_053880 crossref_primary_10_1016_j_ccl_2021_04_006 crossref_primary_10_1093_ajh_hpac086 crossref_primary_10_7326_L20_1097 crossref_primary_10_7326_M20_0065 crossref_primary_10_1161_JAHA_123_030142 crossref_primary_10_1161_STROKEAHA_121_034984 crossref_primary_10_1210_js_2019_00145 crossref_primary_10_1093_eurjpc_zwaa124 crossref_primary_10_1186_s13063_025_08719_8 crossref_primary_10_38109_2075_082X_2024_4_5_109 crossref_primary_10_1161_STROKEAHA_120_033990 crossref_primary_10_1111_bcp_14825 crossref_primary_10_1038_s41574_022_00730_2 crossref_primary_10_1038_s41440_019_0327_2 crossref_primary_10_1161_HYPERTENSIONAHA_125_24648 crossref_primary_10_1007_s11906_019_0974_3 crossref_primary_10_1016_j_ejmech_2024_116521 crossref_primary_10_1097_MNH_0000000000000578 crossref_primary_10_1111_jch_14556 crossref_primary_10_1080_14656566_2019_1707183 crossref_primary_10_1007_s11560_022_00584_9 crossref_primary_10_1161_HYPERTENSIONAHA_118_12242 crossref_primary_10_1161_HYPERTENSIONAHA_125_24871 crossref_primary_10_3390_jcdd9030072 crossref_primary_10_1007_s11906_022_01177_6 crossref_primary_10_1080_14779072_2020_1732206 crossref_primary_10_3390_biomedicines13010053 crossref_primary_10_1093_ajh_hpac079 crossref_primary_10_3390_diagnostics10080545 crossref_primary_10_1007_s00508_019_01565_0 crossref_primary_10_1016_j_cpcardiol_2024_102922 crossref_primary_10_1097_HJH_0000000000001940 crossref_primary_10_1016_j_cjca_2020_02_083 crossref_primary_10_1161_CIRCULATIONAHA_124_073507 crossref_primary_10_1186_s40885_023_00255_4 crossref_primary_10_1016_j_cjca_2020_02_086 crossref_primary_10_1038_s41371_024_00983_6 crossref_primary_10_1161_HYPERTENSIONAHA_119_14359 crossref_primary_10_1080_07853890_2022_2044510 crossref_primary_10_3390_ijms23052658 crossref_primary_10_1016_j_mehy_2023_111234 crossref_primary_10_1038_s41371_023_00875_1 crossref_primary_10_1161_HYPERTENSIONAHA_124_24153 crossref_primary_10_1097_HJH_0000000000002103 crossref_primary_10_1016_j_cpcardiol_2021_100859 crossref_primary_10_1136_postgradmedj_2020_139701 crossref_primary_10_1093_ajh_hpy156 crossref_primary_10_1210_clinem_dgab348 crossref_primary_10_26599_1671_5411_2024_06_001 crossref_primary_10_1016_j_jchf_2020_04_011 crossref_primary_10_1016_j_eprac_2024_04_014 crossref_primary_10_1016_j_jacc_2025_05_007 crossref_primary_10_1016_j_rec_2018_12_001 crossref_primary_10_1161_HYPERTENSIONAHA_122_19159 crossref_primary_10_1007_s11906_019_1013_0 crossref_primary_10_1210_endrev_bnad024 crossref_primary_10_2147_VHRM_S383007 crossref_primary_10_1161_STROKEAHA_120_029679 crossref_primary_10_1056_NEJMoa2213169 crossref_primary_10_1007_s11906_021_01130_z crossref_primary_10_1161_HYPERTENSIONAHA_118_12191 crossref_primary_10_1038_s41581_019_0145_4 crossref_primary_10_1177_20406223221102754 crossref_primary_10_1016_j_cger_2024_04_005 crossref_primary_10_1210_clinem_dgaa606 crossref_primary_10_1016_j_jchf_2025_02_021 crossref_primary_10_1056_NEJMoa2507109 crossref_primary_10_1001_jamainternmed_2024_1455 crossref_primary_10_1016_j_cjca_2020_02_066 crossref_primary_10_1161_CIRCGEN_118_002213 crossref_primary_10_1152_ajprenal_00268_2023 crossref_primary_10_7326_M20_4873 crossref_primary_10_1111_imj_16189 crossref_primary_10_1097_HCR_0000000000000801 crossref_primary_10_1001_jama_2025_5129 crossref_primary_10_1093_eurjpc_zwab154 crossref_primary_10_3389_fendo_2021_631848 crossref_primary_10_1093_ajh_hpaf134 crossref_primary_10_1053_j_ajkd_2023_01_447 crossref_primary_10_1038_s41371_025_01021_9 crossref_primary_10_1097_MNH_0000000000000702 crossref_primary_10_1016_S0140_6736_24_02755_7 crossref_primary_10_1007_s40620_019_00617_y crossref_primary_10_1007_s00467_019_04427_z crossref_primary_10_1093_ajh_hpad118 crossref_primary_10_1038_s41440_022_00923_2 crossref_primary_10_1097_HJH_0000000000002088 crossref_primary_10_2147_VHRM_S422773 crossref_primary_10_1016_j_microc_2021_106983 crossref_primary_10_1093_ehjcvp_pvz057 crossref_primary_10_1016_j_ando_2020_03_009 crossref_primary_10_1177_1715163520975809 crossref_primary_10_1007_s11906_019_0911_5 crossref_primary_10_1172_JCI153202 crossref_primary_10_1007_s11906_020_01081_x crossref_primary_10_3389_fendo_2021_625457 crossref_primary_10_1097_MNH_0000000000001067 crossref_primary_10_1016_j_ejim_2023_12_026 crossref_primary_10_1016_S2213_8587_18_30173_6 crossref_primary_10_1161_CIRCULATIONAHA_123_066389 crossref_primary_10_36290_int_2018_030 crossref_primary_10_1002_ehf2_14086 crossref_primary_10_1007_s13730_024_00934_7 crossref_primary_10_1161_CIRCHEARTFAILURE_119_006638 crossref_primary_10_1097_CRD_0000000000000665 crossref_primary_10_1210_clinem_dgaf284
ContentType	Journal Article
Contributor	Melville, V Balakrishnan, K Saxena, M Wilson, R Schumann, A Kean, S McGinnis, A Coughlan, C Hobbs, R Hobbs, L Markandu, N Zak, A Hood, S Mackay, J Burton, T Papworth, R Myint, K S Enobakhare, E Kwok, S White, C Muir, S Nazir, S MacIntyre, I McCann, G D'Souza, R Palmer, J Rutkowski, K Collier, D Cannon, J Findlay, E Helmy, J McCallum, L Soran, H Webb, A Gupta, P Stanley, A Helmy, C Gardiner-Hill, C Iles, R Lacy, P Martin, U Thom, S
Contributor_xml	– sequence: 1 givenname: K surname: Balakrishnan fullname: Balakrishnan, K – sequence: 2 givenname: T surname: Burton fullname: Burton, T – sequence: 3 givenname: J surname: Cannon fullname: Cannon, J – sequence: 4 givenname: D surname: Collier fullname: Collier, D – sequence: 5 givenname: C surname: Coughlan fullname: Coughlan, C – sequence: 6 givenname: R surname: D'Souza fullname: D'Souza, R – sequence: 7 givenname: E surname: Enobakhare fullname: Enobakhare, E – sequence: 8 givenname: E surname: Findlay fullname: Findlay, E – sequence: 9 givenname: C surname: Gardiner-Hill fullname: Gardiner-Hill, C – sequence: 10 givenname: P surname: Gupta fullname: Gupta, P – sequence: 11 givenname: J surname: Helmy fullname: Helmy, J – sequence: 12 givenname: C surname: Helmy fullname: Helmy, C – sequence: 13 givenname: L surname: Hobbs fullname: Hobbs, L – sequence: 14 givenname: R surname: Hobbs fullname: Hobbs, R – sequence: 15 givenname: S surname: Hood fullname: Hood, S – sequence: 16 givenname: R surname: Iles fullname: Iles, R – sequence: 17 givenname: S surname: Kean fullname: Kean, S – sequence: 18 givenname: S surname: Kwok fullname: Kwok, S – sequence: 19 givenname: P surname: Lacy fullname: Lacy, P – sequence: 20 givenname: I surname: MacIntyre fullname: MacIntyre, I – sequence: 21 givenname: J surname: Mackay fullname: Mackay, J – sequence: 22 givenname: N surname: Markandu fullname: Markandu, N – sequence: 23 givenname: U surname: Martin fullname: Martin, U – sequence: 24 givenname: L surname: McCallum fullname: McCallum, L – sequence: 25 givenname: G surname: McCann fullname: McCann, G – sequence: 26 givenname: A surname: McGinnis fullname: McGinnis, A – sequence: 27 givenname: V surname: Melville fullname: Melville, V – sequence: 28 givenname: S surname: Muir fullname: Muir, S – sequence: 29 givenname: K S surname: Myint fullname: Myint, K S – sequence: 30 givenname: S surname: Nazir fullname: Nazir, S – sequence: 31 givenname: J surname: Palmer fullname: Palmer, J – sequence: 32 givenname: R surname: Papworth fullname: Papworth, R – sequence: 33 givenname: K surname: Rutkowski fullname: Rutkowski, K – sequence: 34 givenname: M surname: Saxena fullname: Saxena, M – sequence: 35 givenname: A surname: Schumann fullname: Schumann, A – sequence: 36 givenname: H surname: Soran fullname: Soran, H – sequence: 37 givenname: A surname: Stanley fullname: Stanley, A – sequence: 38 givenname: S surname: Thom fullname: Thom, S – sequence: 39 givenname: A surname: Webb fullname: Webb, A – sequence: 40 givenname: C surname: White fullname: White, C – sequence: 41 givenname: R surname: Wilson fullname: Wilson, R – sequence: 42 givenname: A surname: Zak fullname: Zak, A
Copyright	Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Copyright_xml	– notice: Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
CorporateAuthor	British Hypertension Society programme of Prevention And Treatment of Hypertension With Algorithm based Therapy (PATHWAY) Study Group
CorporateAuthor_xml	– name: British Hypertension Society programme of Prevention And Treatment of Hypertension With Algorithm based Therapy (PATHWAY) Study Group
DBID	CGR CUY CVF ECM EIF NPM 7X8
DOI	10.1016/S2213-8587(18)30071-8
DatabaseName	Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic
DatabaseTitle	MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic
DatabaseTitleList	MEDLINE MEDLINE - Academic
Database_xml	– sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database
DeliveryMethod	no_fulltext_linktorsrc
Discipline	Medicine
EISSN	2213-8595
ExternalDocumentID	29655877
Genre	Research Support, Non-U.S. Gov't Journal Article
GrantInformation	British Heart Foundation and UK National Institute for Health Research.
GrantInformation_xml	– fundername: British Heart Foundation grantid: SP/08/002 – fundername: Medical Research Council grantid: MC_PC_13090
GroupedDBID	-RU .1- .FO 0R~ 1P~ 4.4 457 53G AAEDT AAEDW AALRI AAMRU AAQFI AAQQT AAXUO ABUDA ACGFS ACVFH ADBBV ADCNI AENEX AFRHN AFTJW AGCQF AITUG AJUYK ALMA_UNASSIGNED_HOLDINGS AMRAJ APXCP CGR CUY CVF EBS ECM EFKBS EIF EJD FDB GBLVA HZ~ NPM O9- OB0 ON- ROL Z5R 7X8
ID	FETCH-LOGICAL-c587t-b0e46c3cb251903528b31a9d9c7c22c2fe634c5e7a390eb18af9f2b19a7574ab2
IEDL.DBID	7X8
ISICitedReferencesCount	225
ISICitedReferencesURI	http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000433066700021&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D
ISSN	2213-8595
IngestDate	Mon Sep 29 02:35:53 EDT 2025 Mon Jul 21 06:03:08 EDT 2025
IsDoiOpenAccess	false
IsOpenAccess	true
IsPeerReviewed	true
IsScholarly	true
Issue	6
Language	English
License	Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
LinkModel	DirectLink
MergedId	FETCHMERGED-LOGICAL-c587t-b0e46c3cb251903528b31a9d9c7c22c2fe634c5e7a390eb18af9f2b19a7574ab2
Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
OpenAccessLink	http://www.thelancet.com/article/S2213858718300718/pdf
PMID	29655877
PQID	2025806779
PQPubID	23479
ParticipantIDs	proquest_miscellaneous_2025806779 pubmed_primary_29655877
PublicationCentury	2000
PublicationDate	2018-06-00 20180601
PublicationDateYYYYMMDD	2018-06-01
PublicationDate_xml	– month: 06 year: 2018 text: 2018-06-00
PublicationDecade	2010
PublicationPlace	England
PublicationPlace_xml	– name: England
PublicationTitle	The lancet. Diabetes & endocrinology
PublicationTitleAlternate	Lancet Diabetes Endocrinol
PublicationYear	2018
References	30053984 - Lancet Diabetes Endocrinol. 2018 Aug;6(8):600-601. doi: 10.1016/S2213-8587(18)30174-8. 30053988 - Lancet Diabetes Endocrinol. 2018 Aug;6(8):e16. doi: 10.1016/S2213-8587(18)30211-0. 29655878 - Lancet Diabetes Endocrinol. 2018 Jun;6(6):431-433. doi: 10.1016/S2213-8587(18)30080-9. 30053983 - Lancet Diabetes Endocrinol. 2018 Aug;6(8):599-600. doi: 10.1016/S2213-8587(18)30173-6.
References_xml	– reference: 30053983 - Lancet Diabetes Endocrinol. 2018 Aug;6(8):599-600. doi: 10.1016/S2213-8587(18)30173-6. – reference: 30053984 - Lancet Diabetes Endocrinol. 2018 Aug;6(8):600-601. doi: 10.1016/S2213-8587(18)30174-8. – reference: 29655878 - Lancet Diabetes Endocrinol. 2018 Jun;6(6):431-433. doi: 10.1016/S2213-8587(18)30080-9. – reference: 30053988 - Lancet Diabetes Endocrinol. 2018 Aug;6(8):e16. doi: 10.1016/S2213-8587(18)30211-0.
SSID	ssj0001053680
Score	2.5800529
Snippet	In the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did...
SourceID	proquest pubmed
SourceType	Aggregation Database Index Database
StartPage	464
SubjectTerms	Aldosterone - metabolism Amiloride - therapeutic use Antihypertensive Agents - therapeutic use Bisoprolol - therapeutic use Blood Pressure - drug effects Doxazosin - therapeutic use Female Hemodynamics - drug effects Humans Hypertension - drug therapy Male Middle Aged Randomized Controlled Trials as Topic Spironolactone - therapeutic use
Title	Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies
URI	https://www.ncbi.nlm.nih.gov/pubmed/29655877 https://www.proquest.com/docview/2025806779
Volume	6
WOSCitedRecordID	wos000433066700021&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D
hasFullText
inHoldings	1
isFullTextHit
isPrint
link	http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV1LSwMxEA6-EC--3w8ieFAw2M0-kvUiRRQPWgpWrKeSZLO0h2Zrt_Xn-FudyW7pSRC87GHZZIdkMplvnoRc2ChTuQ4441HcYJHUAdNwMBgCn4bhSRzlvmT-s2i1ZLebtmuDW1mHVc5kohfUWWHQRo4gPZZY7iy9G30y7BqF3tW6hcYiWQ5BlUGuFl05t7EAhyW-eRrnQciwlNc8iefmtX4pxWUgr0K8bJn8XdH0F87jxn9J3STrtapJmxVvbJEF67bJ6kvtTN8h3w8O5sLsP6pcRvvKDousalBPq3zgkg4cBTyOOqab0D5g1rGPeC_ctR_jw96pj6Wdji1-igG3MG5SUHThFw6Qs8F637QYU7SlAJ2ZvaWgdtJ2s_P03vxgnA4t_m9QDktagiCrQht3ydvjQ-f-idXtGpiBNZww3bBRYkKjMRkWy6xKHQYqzVIjDOeG5zYJIxNbocK0AVeEVHmacx2kSsQiUprvkSUHBB0QCiCLw3RKZ6jhRbE2gTKx0IDXQx6Y5JCcz1a-B8cBfRzK2WJa9uZrf0j2q-3rjaq6HT2eJjFQKo7-MPqYrIFqJKugsBOynIMwsKdkxXxNBuX4zPMZPFvtlx_td94O
linkProvider	ProQuest
openUrl	ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Endocrine+and+haemodynamic+changes+in+resistant+hypertension%2C+and+blood+pressure+responses+to+spironolactone+or+amiloride%3A+the+PATHWAY-2+mechanisms+substudies&rft.jtitle=The+lancet.+Diabetes+%26+endocrinology&rft.au=Williams%2C+Bryan&rft.au=MacDonald%2C+Thomas+M&rft.au=Morant%2C+Steve+V&rft.au=Webb%2C+David+J&rft.date=2018-06-01&rft.eissn=2213-8595&rft.volume=6&rft.issue=6&rft.spage=464&rft_id=info:doi/10.1016%2FS2213-8587%2818%2930071-8&rft_id=info%3Apmid%2F29655877&rft_id=info%3Apmid%2F29655877&rft.externalDocID=29655877
thumbnail_l	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=2213-8595&client=summon
thumbnail_m	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=2213-8595&client=summon
thumbnail_s	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=2213-8595&client=summon