Optimum Treatment for Drug-Resistant Hypertension
- Conditions
- Hypertension, Resistant to Conventional Therapy
- Interventions
- Registration Number
- NCT02369081
- Lead Sponsor
- University of Cambridge
- Brief 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.
- Detailed Description
In published surveys throughout the world the majority of patients with hypertension do not achieve target blood pressure. According to most guidelines including NICE, target blood pressure is 130/80 mmHg in patients with diabetes, 140/90 mmHg in other patients. In the UK there are currently at least 3 million people with treated hypertension whose blood pressure is not controlled. A significant number of these patients will have drug resistant hypertension, defined as:
"a blood pressure that is not adequately controlled to recommended treatment targets despite treatment with maximal recommended and tolerated doses of 3 drugs according to the current BHS/NICE guidelines and treatment algorithm, i.e. (\*ACE-inhibitor or \*ARB or direct renin inhibitor + \*CCB + Diuretic (any diuretic except spironolactone), i.e. A+C+D)".
(\*where ACE-inhibitor=angiotensin converting enzyme inhibitor, ARB=angiotensin receptor blocker, CCB=calcium channel blocker)
The causes of treatment resistance are unknown, and the choice of fourth-line drug almost entirely empirical. At present there is little comparative data for available drugs. There is considerable evidence pointing to Na+ retention as a common culprit, and some data supporting additional diuretics, or alpha blockade in resistant hypertension, though mainly added to two rather than three drugs.20,29,30 A retrospective analysis of two-drug combinations in trials reported that it makes no difference what is combined with what. 31 However, this conclusion conflicts with the view that drugs for hypertension fall into two main categories, acting respectively on the renin and volume components of hypertension, and that most benefit can be derived from combining drugs from different categories.10,32
Despite the successful adoption of the BHS/NICE treatment algorithm for the treatment of hypertension, there remains substantial clinical uncertainty about the preferred clinical management of people with drug resistant hypertension. This is an important question because such patients are at the highest risk for cardiovascular events. The current guidelines acknowledge that there is currently no adequate clinical trial evidence upon which to base recommendations for the preferred 4th line drug treatment for those with resistant hypertension.
It is possible that it makes no difference what drug is added as fourth-line treatment and that the response, on average, will be the same for all classes. Alternatively, it is also possible that one class of drug will always be superior to all the others because the mechanism underpinning resistant hypertension is common to all patients. In this regard, a popular view is that resistant hypertension is invariably due to excessive sodium retention and thus "further diuretic therapy" will always be the most effective treatment. A third possibility is that resistant hypertension is a heterogeneous state and that the study of average responses in cohorts in clinical studies masks substantial individual patient differences.
With regard to this, this study will address the hypothesis that the renin status of the patient defines the response to 4th line treatment in resistant hypertension, i.e. that low renin predicts sodium retention and the best response to diuretic therapy, whereas high renin predicts a better response to drugs that suppress renin, i.e. a β-blocker.
Hypothesis and Novel Aspects of the Trial
The primary hypothesis of the study is that the commonest cause of resistant hypertension is excessive Na+-retention, and that further diuretic therapy (spironolactone used in this study) will be superior to other potential "add-on drugs" for people with inadequate blood pressure control despite treatment with optimal or highest tolerated doses of the three drug classes recommended by the BHS/NICE treatment algorithm, i.e. A+C+D.
The main secondary objective is to use plasma renin measurements to evaluate an 'α, β, ∆' rule for the selection of the 4th line drug for patients with drug resistant hypertension - where α represents α-blockade, β represents β-blockade and ∆ represents "further diuretic therapy" as cited above. The main secondary hypothesis states that plasma renin (measured on a background of 3 drugs, i.e. A+C+D), will predict the most effective 4th line drug. We propose that:
α-blockade will be the most effective 4th line drug at lowering BP in patients in the mid-tertile of plasma renin, expected to be ≥20mU/L but \<100mU/L; β-blockade will be the most effective drug when renin is in the top tertile (expected to be ≥100Mu/L) as the drug blocks renin secretion; Further diuretic therapy with spironolactone will be most effective when plasma renin is in the lowest tertile (expected to be \<20mU/L), indicative of excessive sodium retention.
The study will also evaluate whether the routine use of plasma renin to predict best treatment in individual patients with resistant hypertension will be more cost-effective than using further diuretic therapy indiscriminately as the preferred 4th line drug for all patients.
Finally the study will investigate whether non-invasive assessment of haemodynamic parameters indicative of sodium retention and volume status, i.e. cardiac output, peripheral resistance and bioimpedance, can be used to predict the response to each drug in the α, β, ∆ sequence.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 348
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Placebo Placebo Each patient will patients will receive in random order 12 weeks treatment with each of the three active drugs (spironolactone, bisoprolol, doxazosin) or placebo. The dose will be doubled at the six week visit half-way through each phase Doxazosin Doxazosin Each patient will patients will receive in random order 12 weeks treatment with each of the three active drugs (spironolactone, bisoprolol, doxazosin) or placebo. The dose will be doubled at the six week visit half-way through each phase Bisoprolol Bisoprolol Each patient will patients will receive in random order 12 weeks treatment with each of the three active drugs (spironolactone, bisoprolol, doxazosin) or placebo. The dose will be doubled at the six week visit half-way through each phase Spironolactone Spironolactone Each patient will patients will receive in random order 12 weeks treatment with each of the three active drugs (spironolactone, bisoprolol, doxazosin) or placebo. The dose will be doubled at the six week visit half-way through each phase.
- Primary Outcome Measures
Name Time Method Treatment arm comparison according to home blood pressure measurement 48 weeks We will adopt a hierarchical procedure to test, in order, the differences in home systolic BP between spironolactone and
1. placebo
2. the average of the other two active drugs
3. each of the other two drugs. The second and third tests will be carried out if and only if the preceding test(s) are significant (P\<0.05).
We shall use a mixed model to analyse home BP, with unstructured covariances for the repeated measures across the two doses for each treatment within a patient. The model will include terms for gender, age, height, weight, smoking history and a diagnosis of diabetes at baseline. We will also adjust for baseline BP.
- Secondary Outcome Measures
Name Time Method Measurement of plasma renin as predictor of effective treatment 48 weeks The difference in home systolic BP averages between the best drug predicted by the patient's plasma renin (according to the 'α, β, ∆' rule cited above) and further diuretic therapy;ie with spironolactone, which we have predicted will be the most effective treatment on average.
Trial Locations
- Locations (16)
University Hospitals Birmingham NHS Foundation Trust
🇬🇧Birmingham, United Kingdom
University of Birmingham
🇬🇧Birmingham, United Kingdom
University of Cambridge - Addenbrookes Hospital
🇬🇧Cambridge, United Kingdom
Guys and St Thomas' NHS Foundation Trust
🇬🇧London, United Kingdom
NHS Ayrshire
🇬🇧Ayrshire, United Kingdom
NHS Tayside/University of Dundee
🇬🇧Dundee, United Kingdom
Royal Devon & Exeter NHS Foundation Trust
🇬🇧Exeter, United Kingdom
NHS Greater Glasgow and Clyde/University of Glasgow
🇬🇧Glasgow, United Kingdom
NHS Lothian/University of Edinburgh
🇬🇧Edinburgh, United Kingdom
University Hospitals of Leicester NHS Trust
🇬🇧Leicester, United Kingdom
Ixworth GP Practice
🇬🇧Ixworth, United Kingdom
Barts and the London School of Medicine and Dentistry
🇬🇧London, United Kingdom
Imperial College Healthcare NHS Trust
🇬🇧London, United Kingdom
West Hertfordshire Hospitals NHS Trust
🇬🇧Watford, United Kingdom
Norfolk and Norwich University Hospital NHS Trust
🇬🇧Norwich, United Kingdom
Central Manchester University Hospitals NHS Foundation Trust
🇬🇧Manchester, United Kingdom