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

Bryan Williams; Thomas M. MacDonald; Mark Caulfield; J. Kennedy Cruickshank; Gordon McInnes; Peter Sever; David J. Webb; Jackie Salsbury; Steve Morant; Ian Ford; Morris J. Brown

doi:10.1136/bmjopen-2015-008951

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

Bryan Williams (Lead / Corresponding author), Thomas M. MacDonald, Mark Caulfield, J. Kennedy Cruickshank, Gordon McInnes, Peter Sever, David J. Webb, Jackie Salsbury, Steve Morant, Ian Ford, Morris J. Brown

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English
Article number	e008951
Number of pages	13
Journal	BMJ Open
Volume	5
Issue number	8
DOIs	https://doi.org/10.1136/bmjopen-2015-008951
Publication status	Published - 7 Aug 2015

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Williams, B., MacDonald, T. M., Caulfield, M., Cruickshank, J. K., McInnes, G., Sever, P., Webb, D. J., Salsbury, J., Morant, S., Ford, I., & Brown, M. J. (2015). 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. BMJ Open, 5(8), Article e008951. https://doi.org/10.1136/bmjopen-2015-008951

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title = "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",

abstract = "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.",

author = "Bryan Williams and MacDonald, {Thomas M.} and Mark Caulfield and Cruickshank, {J. Kennedy} and Gordon McInnes and Peter Sever and Webb, {David J.} and Jackie Salsbury and Steve Morant and Ian Ford and Brown, {Morris J.}",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.",

year = "2015",

month = aug,

day = "7",

doi = "10.1136/bmjopen-2015-008951",

language = "English",

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Williams, B, MacDonald, TM, Caulfield, M, Cruickshank, JK, McInnes, G, Sever, P, Webb, DJ, Salsbury, J, Morant, S, Ford, I & Brown, MJ 2015, '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', BMJ Open, vol. 5, no. 8, e008951. https://doi.org/10.1136/bmjopen-2015-008951

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. / Williams, Bryan (Lead / Corresponding author); MacDonald, Thomas M.; Caulfield, Mark et al.
In: BMJ Open, Vol. 5, No. 8, e008951, 07.08.2015.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Prevention And Treatment of Hypertension With Algorithm-based therapy (PATHWAY) number 2

T2 - protocol for a randomised crossover trial to determine optimal treatment for drug-resistant hypertension

AU - Williams, Bryan

AU - MacDonald, Thomas M.

AU - Caulfield, Mark

AU - Cruickshank, J. Kennedy

AU - McInnes, Gordon

AU - Sever, Peter

AU - Webb, David J.

AU - Salsbury, Jackie

AU - Morant, Steve

AU - Ford, Ian

AU - Brown, Morris J.

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

PY - 2015/8/7

Y1 - 2015/8/7

N2 - 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.

AB - 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.

U2 - 10.1136/bmjopen-2015-008951

DO - 10.1136/bmjopen-2015-008951

M3 - Article

C2 - 26253568

SN - 2044-6055

VL - 5

JO - BMJ Open

JF - BMJ Open

IS - 8

M1 - e008951

ER -

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

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