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.