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: BACKGROUND
  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
  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.
  
  
  BACKGROUND
  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.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT02369081, EUDract number: 2008-007149-30.
authors.affiliation: Institute of Cardiovascular Sciences University College London (UCL) and National Institute for Health Research (NIHR) UCL/UCL Hospitals Biomedical Research Centre, London, UK.
authors.forename: Bryan
authors.initials: B
authors.lastname: Williams
authors.affiliation: Medicines Monitoring Unit, Medical Research Institute, University of Dundee, Dundee, Tayside, UK.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: MacDonald
authors.affiliation: William Harvey Institute, QMUL, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Caulfield
authors.affiliation: Cardiovascular Medicine & Diabetes, King's College London, London, UK.
authors.forename: J Kennedy
authors.initials: JK
authors.lastname: Cruickshank
authors.affiliation: Institute of Cardiovascular Medical Sciences, Western Infirmary, University of Glasgow, Glasgow, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: McInnes
authors.affiliation: Centre of Circulatory Health, Imperial College, London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Sever
authors.affiliation: Clinical Pharmacology Unit, University of Edinburgh, Edinburgh, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Webb
authors.affiliation: Clinical Pharmacology Unit, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
authors.forename: Jackie
authors.initials: J
authors.lastname: Salsbury
authors.affiliation: Clinical Pharmacology Unit, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Morant
authors.affiliation: Robertson Centre, University of Glasgow, Glasgow, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Ford
authors.affiliation: Clinical Pharmacology Unit, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Brown
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000465:Algorithms; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D002985:Clinical Protocols; D018592:Cross-Over Studies; D004232:Diuretics / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D013148:Spironolactone / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004232:Diuretics; D013148:Spironolactone
keywords: Drug Treatment; Resistant Hypertension