Comparison of single and combination diuretics on glucose tolerance (PATHWAY-3):protocol for a randomised double-blind trial in patients with essential hypertension

INTRODUCTION: Thiazide diuretics are associated with increased risk of diabetes mellitus. This risk may arise from K(+)-depletion. We hypothesised that a K(+)-sparing diuretic will improve glucose tolerance, and that combination of low-dose thiazide with K(+)-sparing diuretic will improve both blood pressure reduction and glucose tolerance, compared to a high-dose thiazide.METHODS AND ANALYSIS: This is a parallel-group, randomised, double-blind, multicentre trial, comparing hydrochlorothiazide 25-50 mg, amiloride 10-20 mg and combination of both diuretics at half these doses. A single-blind placebo run-in of 1 month is followed by 24 weeks of blinded active treatment. There is forced dose-doubling after 3 months. The Primary end point is the blood glucose 2 h after oral ingestion of a 75 g glucose drink (OGTT), following overnight fasting. The primary outcome is the difference between 2 h glucose at weeks 0, 12 and 24. Secondary outcomes include the changes in home systolic blood pressure (BP) and glycated haemoglobin and prediction of response by baseline plasma renin. Eligibility criteria are: age 18-79, systolic BP on permitted background treatment ≥140 mm Hg and home BP ≥130 mm Hg and one component of the metabolic syndrome additional to hypertension. Principal exclusions are diabetes, estimated-glomerular filtration rate &lt;45 mL/min, abnormal plasma K(+), clinic SBP &gt;200 mm Hg or DBP &gt;120 mm Hg (box 2). The sample size calculation indicates that 486 patients will give 80% power at α=0.01 to detect a difference in means of 1 mmol/L (SD=2.2) between 2 h glucose on hydrochlorothiazide and comparators.ETHICS AND DISSEMINATION: PATHWAY-3 was approved by Cambridge South Ethics Committee, number 09/H035/19. The trial results will be published in a peer-reviewed scientific journal.TRIAL REGISTRATION NUMBERS: Eudract number 2009-010068-41 and clinical trials registration number: NCT02351973.</p

Prevention And Treatment of Hypertension With Algorithm-based therapy (PATHWAY) number 2: protocol for a randomised crossover trial to determine optimal treatment for drug-resistant hypertension.

This is the final published version. It first appeared at http://bmjopen.bmj.com/content/5/8/e008951.full.INTRODUCTION: Resistant hypertension is inadequately controlled blood pressure (BP) despite treatment with at least three BP-lowering drugs. A popular hypothesis is that resistant hypertension is due to excessive Na(+)-retention, and that 'further diuretic therapy' will be superior to alternative add-on drugs. METHODS AND ANALYSIS: Placebo-controlled, random crossover study of fourth-line treatment when added to standard (A+C+D) triple drug therapy: ACE inhibitor or Angiotensin receptor blocker (A) +Calcium channel blocker (C)+Diuretic (D). Patients (aged 18-79 years) with clinical systolic BP ≥ 140 mm Hg (135 mm Hg in diabetics) and Home BP Monitoring (HBPM) systolic BP average ≥ 130 mm Hg on treatment for at least 3 months with maximum tolerated doses of A+C+D are randomised to four consecutive randomly allocated 12-week treatment cycles with an α-blocker, β-blocker, spironolactone and placebo. The hierarchical coprimary end point is the difference in HBPM average systolic BP between (in order) spironolactone and placebo, spironolactone and the average of the other two active drugs, spironolactone and each of the other two drugs. A key secondary outcome is to determine whether plasma renin predicts the BP response to the different drugs. A sample size of 346 (allowing 15% dropouts) will confer 90% power to detect a 3 mm Hg HBPM average systolic BP difference between any two drugs. The study can also detect a 6 mm Hg difference in HBPM average systolic BP between each patient's best and second-best drug predicted by tertile of plasma renin. ETHICS AND DISSEMINATION: The study was initiated in May 2009 and results are expected in 2015. These will provide RCT evidence to support future guideline recommendations for optimal drug treatment of resistant hypertension. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT02369081, EUDract number: 2008-007149-30.The study is funded by a special project grant from the British Heart Foundation (number SP/08/002). Further funding is provided by the National Institute for Health Research (NIHR) Comprehensive Local Research Networks. BW is supported by the NIHR UCL/UCL Hospitals Biomedical Research Centre

Monotherapy versus dual therapy for the initial treatment of hypertension (PATHWAY-1): a randomised double-blind controlled trial.

This is the final version of the article. It first appeared from BMJ via http://dx.doi.org/10.1136/bmjopen-2015-007645INTRODUCTION: Previous studies have suggested that more intensive initial therapy for hypertension results in better long-term blood pressure (BP) control. We test this hypothesis comparing initial monotherapy with dual therapy in the management of essential hypertension. METHODS AND ANALYSIS: The study is a prospective, multicentre, double-blind, active-controlled trial in patients with essential hypertension. Around 50% of patients studied will be newly diagnosed and the others will be known hypertensives who previously received only monotherapy. The trial is divided into three phases as follows: Phase 1 (Week 0-Week 16): Randomised, parallel-group, masked assignation to either combination or monotherapy. Phase 2 (Week 17-Week 32): Open-label combination therapy. Phase 3 (Week 33-Week 52): Open-label combination therapy plus open-label add-on (if BP is above 140/90 mm Hg). Hierarchical primary end points are: a comparison of home BP (home systolic blood pressure (HSBP)) averaged over the duration of phase 1 and 2 in the combination versus monotherapy arms. If combination is superior in this analysis, then the averaged mean HSBP between initial monotherapy and initial combination therapy at the end of phase 2 will be compared. Secondary end points include: BP control at 1 year; the role of age, baseline renin, sodium status, plasma volume, haemodynamic compensation and peripheral resistance on BP control; validation of the National Institute for Clinical Excellence/British Hypertension Society joint guideline algorithm; safety and tolerability of combination therapy; and the impact of combination versus monotherapy on left ventricular mass and aortic pulse wave velocity. A sample size of 536 (268 in each group) will have 90% power to detect a difference in means of 4 mm Hg. ETHICS AND DISSEMINATION: PATHWAY 1 was approved by UK ethics (REC Reference 09/H0308/132). Trial results will be published and all participating subjects will be informed of the results. TRIAL REGISTRATION NUMBER: UKCRN 4499 and EudraCT number 2008-007749-29 registered 27/08/2009.Funding statement The study is funded by a special project grant from the British Heart Foundation (number SP/08/002). Further funding is provided by Comprehensive Local Research Networks. The losartan and losartan-HCTZ were a generous gift from Dr Paul Robinson, Merck Sharpe Dohme, UK. Acknowledgements BW, PS, MC and MJB are NIHR Senior Investigators

Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.

This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/S0140-6736(15)00257-3BACKGROUND: Optimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by excessive sodium retention, and that spironolactone would therefore be superior to non-diuretic add-on drugs at lowering blood pressure. METHODS: In this double-blind, placebo-controlled, crossover trial, we enrolled patients aged 18-79 years with seated clinic systolic blood pressure 140 mm Hg or greater (or ≥135 mm Hg for patients with diabetes) and home systolic blood pressure (18 readings over 4 days) 130 mm Hg or greater, despite treatment for at least 3 months with maximally tolerated doses of three drugs, from 12 secondary and two primary care sites in the UK. Patients rotated, in a preassigned, randomised order, through 12 weeks of once daily treatment with each of spironolactone (25-50 mg), bisoprolol (5-10 mg), doxazosin modified release (4-8 mg), and placebo, in addition to their baseline blood pressure drugs. Random assignment was done via a central computer system. Investigators and patients were masked to the identity of drugs, and to their sequence allocation. The dose was doubled after 6 weeks of each cycle. The hierarchical primary endpoints were the difference in averaged home systolic blood pressure between spironolactone and placebo, followed (if significant) by the difference in home systolic blood pressure between spironolactone and the average of the other two active drugs, followed by the difference in home systolic blood pressure between spironolactone and each of the other two drugs. Analysis was by intention to treat. The trial is registered with EudraCT number 2008-007149-30, and ClinicalTrials.gov number, NCT02369081. FINDINGS: Between May 15, 2009, and July 8, 2014, we screened 436 patients, of whom 335 were randomly assigned. After 21 were excluded, 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles. The average reduction in home systolic blood pressure by spironolactone was superior to placebo (-8·70 mm Hg [95% CI -9·72 to -7·69]; p<0·0001), superior to the mean of the other two active treatments (doxazosin and bisoprolol; -4·26 [-5·13 to -3·38]; p<0·0001), and superior when compared with the individual treatments; versus doxazosin (-4·03 [-5·04 to -3·02]; p<0·0001) and versus bisoprolol (-4·48 [-5·50 to -3·46]; p<0·0001). Spironolactone was the most effective blood pressure-lowering treatment, throughout the distribution of baseline plasma renin; but its margin of superiority and likelihood of being the best drug for the individual patient were many-fold greater in the lower than higher ends of the distribution. All treatments were well tolerated. In six of the 285 patients who received spironolactone, serum potassium exceeded 6·0 mmol/L on one occasion. INTERPRETATION: Spironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition. FUNDING: The British Heart Foundation and National Institute for Health Research.The study was funded by a special project grant from the British Heart Foundation (number SP/08/002). Further funding was provided by the National Institute for Health Research (NIHR) Comprehensive Local Research Networks. BW, PS, MC, and MJB are NIHR Senior Investigators, and are supported by, respectively, the NIHR UCL/UCL Hospitals Biomedical Research Centre, the Biomedical Research Centre award to Imperial College Healthcare NHS Trust, the NIHR Cardiovascular Biomedical research Unit at St Bartholomew’s Hospital, London, and the NIHR Biomedical Research Centre award to Cambridge University Hospitals NHS Trust. Blinded medication was packed by Alan Wong and colleagues at the Royal Free Hospital pharmac

Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production

Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1 cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production

Amiloride-hydrochlorothiazide versus individual diuretic effects on glucose tolerance and blood pressure (PATHWAY-3): a double-blind randomised trial

This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/S2213-8587(15)00377-0BACKGROUND: Potassium depletion by thiazide diuretics is associated with a rise in blood glucose. We assessed whether addition or substitution of a potassium-sparing diuretic, amiloride, to treatment with a thiazide can prevent glucose intolerance and improve blood pressure control. METHODS: We did a parallel-group, randomised, double-blind trial in 11 secondary and two primary care sites in the UK. Eligible patients were aged 18-80 years; had clinic systolic blood pressure of 140 mm Hg or higher and home systolic blood pressure of 130 mmHg or higher on permitted background drugs of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, β blockers, calcium-channel blockers, or direct renin inhibitors (previously untreated patients were also eligible in specific circumstances); and had at least one component of the metabolic syndrome in addition to hypertension. Patients with known diabetes were excluded. Patients were randomly assigned (1:1:1) to 24 weeks of daily oral treatment with starting doses of 10 mg amiloride, 25 mg hydrochlorothiazide, or 5 mg amiloride plus 12·5 mg hydrochlorothiazide; all doses were doubled after 12 weeks. Random assignment was done via a central computer system. Both participants and investigators were masked to assignment. Our hierarchical primary endpoints, assessed on a modified intention-to-treat basis at 12 and 24 weeks, were the differences from baseline in blood glucose measured 2 h after a 75 g oral glucose tolerance test (OGTT), compared first between the hydrochlorothiazide and amiloride groups, and then between the hydrochlorothiazide and combination groups. A key secondary endpoint was change in home systolic blood pressure at 12 and 24 weeks. This trial is registered with ClinicalTrials.gov, number NCT00797862, and the MHRA, Eudract number 2009-010068-41, and is now complete. FINDINGS: Between Nov 18, 2009, and Dec 15, 2014, 145 patients were randomly assigned to amiloride, 146 to hydrochlorothiazide, and 150 to the combination group. 132 participants in the amiloride group, 134 in the hydrochlorothiazide group, and 133 in the combination group were included in the modified intention-to-treat analysis. 2 h glucose concentrations after OGTT, averaged at 12 and 24 weeks, were significantly lower in the amiloride group than in the hydrochlorothiazide group (mean difference -0·55 mmol/L [95% CI -0·96 to -0·14]; p=0·0093) and in the combination group than in the hydrochlorothiazide group (-0·42 mmol/L [-0·84 to -0·004]; p=0·048). The mean reduction in home systolic blood pressure during 24 weeks did not differ significantly between the amiloride and hydrochlorothiazide groups, but the fall in blood pressure in the combination group was significantly greater than that in the hydrochlorothiazide group (p=0·0068). Hyperkalaemia was reported in seven (4·8%) patients in the amiloride group and three (2·3%) patients in the combination group; the highest recorded potassium concentration was 5·8 mmol/L in a patient in the amiloride group. 13 serious adverse events occurred but the frequency did not differ significantly between groups. INTERPRETATION: The combination of amiloride with hydrochlorothiazide, at doses equipotent on blood pressure, prevents glucose intolerance and improves control of blood pressure compared with montherapy with either drug. These findings, together with previous data about morbidity and mortality for the combination, support first-line use of amiloride plus hydrochlorothiazide in hypertensive patients who need treatment with a diuretic. FUNDING: British Heart Foundation and National Institute for Health Research.The study was funded by a special project grant from the British Heart Foundation (number SP/08/002), and support from National Institute of Health Research Comprehensive Local Research Networks

[11C]metomidate PET-CT versus adrenal vein sampling for diagnosing surgically curable primary aldosteronism: a prospective, within-patient trial.

Primary aldosteronism (PA) due to a unilateral aldosterone-producing adenoma is a common cause of hypertension. This can be cured, or greatly improved, by adrenal surgery. However, the invasive nature of the standard pre-surgical investigation contributes to fewer than 1% of patients with PA being offered the chance of a cure. The primary objective of our prospective study of 143 patients with PA ( NCT02945904 ) was to compare the accuracy of a non-invasive test, [11C]metomidate positron emission tomography computed tomography (MTO) scanning, with adrenal vein sampling (AVS) in predicting the biochemical remission of PA and the resolution of hypertension after surgery. A total of 128 patients reached 6- to 9-month follow-up, with 78 (61%) treated surgically and 50 (39%) managed medically. Of the 78 patients receiving surgery, 77 achieved one or more PA surgical outcome criterion for success. The accuracies of MTO at predicting biochemical and clinical success following adrenalectomy were, respectively, 72.7 and 65.4%. For AVS, the accuracies were 63.6 and 61.5%. MTO was not significantly superior, but the differences of 9.1% (95% confidence interval = -6.5 to 24.1%) and 3.8% (95% confidence interval = -11.9 to 9.4) lay within the pre-specified -17% margin for non-inferiority (P = 0.00055 and P = 0.0077, respectively). Of 24 serious adverse events, none was considered related to either investigation and 22 were fully resolved. MTO enables non-invasive diagnosis of unilateral PA

Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production.

Funder: DH | NIHR | Efficacy and Mechanism Evaluation Programme (NIHR Efficacy and Mechanism Evaluation Programme); doi: https://doi.org/10.13039/501100001922Funder: British Heart Foundation (BHF); doi: https://doi.org/10.13039/501100000274Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: Royal Society-Newton Advanced Research Fellow (NA170257/FF-2018-033Funder: Japan Society for the Promotion of Science KAKENHI grants 17K08680Funder: DH | NIHR | Health Services Research Programme (NIHR Health Services Research Programme); doi: https://doi.org/10.13039/501100001923Funder: NIHR Translational ResearchFunder: Biomedical Research Council, SingaporeFunder: the European Research Council under the European Union’s Horizon 2020 research and innovation program. Grant agreement No. 694913Funder: Japan Society for the Promotion of Science KAKENHI grants. Grant ref no. 18K07414Funder: European Research Council under the European Union’s Horizon 2020 research and innovation program. Grant agreement No. 633983Funder: Japan Society for the Promotion of Science KAKENHI grants. Grant ref. 18K07049 and 15K15113 Ministry of Education, Culture, Sports, Science and Technology-Supported Program for the Strategic Research Foundation at Private Universities 2015-19Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1 cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production