Ignite Creation Date:
2024-05-06 @ 3:44 AM
Last Modification Date:
2024-10-26 @ 11:38 AM
Study NCT ID:
NCT02369081
Status:
UNKNOWN
Last Update Posted:
2015-07-03
First Post:
2013-06-11
Brief Title:
Optimum Treatment for Drug-Resistant Hypertension
Sponsor:
University of Cambridge
Organization:
University of Cambridge
Study Overview
Official Title:
Optimum Treatment for Drug-Resistant Hypertension
Status:
UNKNOWN
Status Verified Date:
2015-07
Last Known Status:
ACTIVE_NOT_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PATHWAY2
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 ACD 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 α001 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 subjects best and second-best drug predicted by tertile of plasma renin justifying routine use of the measurement in patients with resistant hypertension
Patients will have a BP at entry above target on ABPM or home monitoring despite supervised administration of maximum tolerated doses of ACD 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 α001 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 subjects 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 13080 mmHg in patients with diabetes 14090 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 BHSNICE guidelines and treatment algorithm ie ACE-inhibitor or ARB or direct renin inhibitor CCB Diuretic any diuretic except spironolactone ie ACD
where ACE-inhibitorangiotensin converting enzyme inhibitor ARBangiotensin receptor blocker CCBcalcium 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 drugs202930 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 categories1032
Despite the successful adoption of the BHSNICE 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 ie 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 ie 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 BHSNICE treatment algorithm ie ACD
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 ie ACD 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 20mUL but 100mUL β-blockade will be the most effective drug when renin is in the top tertile expected to be 100MuL 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 20mUL 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 ie cardiac output peripheral resistance and bioimpedance can be used to predict the response to each drug in the α β sequence
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 BHSNICE guidelines and treatment algorithm ie ACE-inhibitor or ARB or direct renin inhibitor CCB Diuretic any diuretic except spironolactone ie ACD
where ACE-inhibitorangiotensin converting enzyme inhibitor ARBangiotensin receptor blocker CCBcalcium 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 drugs202930 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 categories1032
Despite the successful adoption of the BHSNICE 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 ie 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 ie 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 BHSNICE treatment algorithm ie ACD
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 ie ACD 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 20mUL but 100mUL β-blockade will be the most effective drug when renin is in the top tertile expected to be 100MuL 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 20mUL 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 ie cardiac output peripheral resistance and bioimpedance can be used to predict the response to each drug in the α β sequence
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2008-007149-30 | EUDRACT_NUMBER | None | None |