Mechanisms of Refractory Hypertension (Carvedilol)

Study Overview
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Brief Summary
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The purpose of this protocol is test whether patients with hypertension refractory to antihypertensive treatment have evidence of excessive sympathetic (i.e., nervous system) activity.

Detailed Description
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Refractory hypertension refers to high blood pressure that is failing conventional antihypertensive therapies. In a retrospective assessment of such patients in our clinic we observed that resting clinic heart rates were higher in patients with refractory hypertension compared to patients with controlled hypertension. This observation has led to the hypothesis that refractory hypertension is caused by excessive sympathetic output. This protocol is designed to test this hypothesis by comparing the BP response to carvedilol verses chlorthalidone in patients with refractory hypertension. If their extreme treatment resistance is neurogenic is etiology, a significantly larger BP response to carvedilol should occur compared to chlorthalidone.

Conditions
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Hypertensive

Intervention / Treatment
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* Drug: Carvedilol
* Drug: Chlorthalidone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Uncontrolled clinic BP (>140/90 mmHg) Receiving 5 or more antihypertensive agents including an ACE inhibitor or ARB, calcium channel blocker, and chlorthalidone 25 mg Exclusion Criteria: Current use of an alpha or beta or combined alpha-beta antagonist Known allergy to alpha-beta antagonists CKD (eGFR <40 ml/min/m2) MI, stroke or episode of CHF exacerbation within 3 months Bradycardia <50 bpm; history of 2nd or 3rd degree heart block unless treated by a pacemaker Pregnant or breast-feeding women Known hypersensitivity to chlorthalidone or other sulfonamide-derived drugs

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carvedilol<br>Carvedilol CR 40 mg daily in addition to their normal BP medications. Subjects will be seen in follow-up at 2-week intervals for the duration of the 8-week intervention period. If the clinic BP remains elevated (>140/90 mmHg) at any of the follow-up visits, the study medication will be titrated up to carvedilol CR 80 mg daily (subjects will take 2 of the study pills). | Drug: Carvedilol<br>* CR 40 mg daily in addition to normal BP medications<br>|
| Experimental: Chlorthalidone<br>Chlorthalidone 12.5 mg daily in addition to their normal BP medications. Subjects will be seen in follow-up at 2-week intervals for the duration of the 8-week intervention period. If the clinic BP remains elevated (>140/90 mmHg) at any of the follow-up visits, the study medication will be titrated up to chlorthalidone 25 mg daily (subjects will take 2 of the study pills). | Drug: Chlorthalidone<br>* 12.5 mg daily in addition to normal BP medications<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| % of subjects who achieve BP control (<140/90 mm Hg) | BP will be measured 8 weeks after starting carvedilol and after starting chlorthaidone. The percent of subjects with BP of <140/90 mm HG in each group will be reported. | 8 weeks after baseline |