Optimum Treatment for Drug-Resistant Hypertension

Summary

This study was recommended by NICE, as part of its 2006 guidance for the treatment of hypertension, and is urgently required to provide evidence for the treatment recommendations in patients with resistant hypertension. The study will be a randomised placebo-controlled double-blind crossover comparison of an α-blocker (α), β-blocker (β), and K+-sparing diuretic (∆). Patients will have a BP at entry above target on ABPM or home monitoring despite supervised administration of maximum tolerated doses of A+C+D. Over 48 weeks they will then receive, in random order either placebo or two doses each of doxazosin (α), bisoprolol (β) or spironolactone (∆). Each treatment cycle will last 12 weeks, with a forced dose-doubling at 6 weeks. The time course for the study will be similar to study one. 340 patients will provide 90% power, at α=0.01 to detect a 3 mmHg overall difference in home sBP between any one drug and placebo, with spironolactone hypothesized to be best overall. The study will be able to detect a 6 mmHg difference in sBP between each subject's best and second-best drug predicted by tertile of plasma renin, justifying routine use of the measurement in patients with resistant hypertension.

Timeline

Start

2009-05

Primary completion

2015-07

Completion

2015-08

Publications

• Background NICE/BHS. CG34 Hypertension - NICE guideline (all the recommendations). http://www.nice.org.uk/guidance/CG34/niceguidance /pdf/english 2006
• Background Dickerson JE, Hingorani AD, Ashby MJ, Palmer CR, Brown MJ. Optimisation of antihypertensive treatment by crossover rotation of four major classes. Lancet. 1999 Jun 12;353(9169):2008-13. doi: 10.1016/s0140-6736(98)07614-4.
• Background Deary AJ, Schumann AL, Murfet H, Haydock SF, Foo RS, Brown MJ. Double-blind, placebo-controlled crossover comparison of five classes of antihypertensive drugs. J Hypertens. 2002 Apr;20(4):771-7. doi: 10.1097/00004872-200204000-00037.
• Background Taler SJ, Textor SC, Augustine JE. Resistant hypertension: comparing hemodynamic management to specialist care. Hypertension. 2002 May;39(5):982-8. doi: 10.1161/01.hyp.0000016176.16042.2f.
• Background Kaplan NM. Resistant hypertension. J Hypertens. 2005 Aug;23(8):1441-4. doi: 10.1097/01.hjh.0000174968.72212.ac.
• Background Black HR, Keck M, Meredith P, Bullen K, Quinn S, Koren A. Controlled-release doxazosin as combination therapy in hypertension: the GATES study. J Clin Hypertens (Greenwich). 2006 Mar;8(3):159-66; quiz 167-8. doi: 10.1111/j.1524-6175.2006.04811.x.
• Background Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003 Jun 28;326(7404):1427. doi: 10.1136/bmj.326.7404.1427.
• Background Brown MJ, Cruickshank JK, Dominiczak AF, MacGregor GA, Poulter NR, Russell GI, Thom S, Williams B; Executive Committee, British Hypertension Society. Better blood pressure control: how to combine drugs. J Hum Hypertens. 2003 Feb;17(2):81-6. doi: 10.1038/sj.jhh.1001511.
• Williams B, MacDonald TM, Morant SV, Webb DJ, Sever P, McInnes GT, Ford I, Cruickshank JK, Caulfield MJ, Padmanabhan S, Mackenzie IS, Salsbury J, Brown MJ; British Hypertension Society programme of Prevention And Treatment of Hypertension With Algorithm based Therapy (PATHWAY) Study Group. Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies. Lancet Diabetes Endocrinol. 2018 Jun;6(6):464-475. doi: 10.1016/S2213-8587(18)30071-8. Epub 2018 Apr 11.
• Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, McInnes G, Ford I, Cruickshank JK, Caulfield MJ, Salsbury J, Mackenzie I, Padmanabhan S, Brown MJ; British Hypertension Society's PATHWAY Studies Group. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015 Nov 21;386(10008):2059-2068. doi: 10.1016/S0140-6736(15)00257-3. Epub 2015 Sep 20.
• Williams B, MacDonald TM, Caulfield M, Cruickshank JK, McInnes G, Sever P, Webb DJ, Salsbury J, Morant S, Ford I, Brown MJ. 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. 2015 Aug 7;5(8):e008951. doi: 10.1136/bmjopen-2015-008951.

Drugs

Indications