Pharmacogenomic Evaluation of Antihypertensive Responses 2

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

839 participants

Study Classification

INTERVENTIONAL

Study Start Date

2010-08-31

Study Completion Date

2014-04-30

Brief Summary

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There are many medications available for the treatment of high blood pressure (hypertension), but finding the right one for a specific patient can be challenging. In fact, it is estimated that less than 50% of people with hypertension have their blood pressure under control. The hypothesis is that genetic differences between individuals influence their response to antihypertensive medications. This study is aimed at determining the genetic factors that may influence a person's response to either a beta-blocker or a thiazide diuretic. The hope is that through this research, the investigators may someday be able to use an individual's genetic information to guide the selection of their blood pressure medicine, leading to better control of blood pressure, and less need for the current trial and error process.

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Detailed Description

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The proposed work should help move toward the long-term goal of selection of antihypertensive drug therapy based on a patient's genetic make-up. Hypertension (HTN) is the most common chronic disease for which drugs are prescribed, and the most prevalent risk factor for heart attack, stroke, renal failure and heart failure. Responses to antihypertensive drug therapy exhibit considerable interpatient variability, contributing to poor rates of HTN control (currently about 40-50% in the US), and frequent nonadherence and dropout from therapy. We propose to identify genetic predictors of the antihypertensive and adverse metabolic responses to two preferred and pharmacodynamically contrasting drugs, a beta-blocker (metoprolol) and a thiazide diuretic (chlorthalidone) in a sequential monotherapy design in 400 hypertensive individuals. Data collected will include home and clinic blood pressure, blood samples for testing for adverse metabolic effects and other biomarkers, RNA, and DNA and urine sample. We will conduct genome-wide association single nucleotide polymorphism (SNP) genotyping and data from the study will be used for replication of findings from the previous PEAR trial, along with new discoveries. The primary aims are to define the genetic determinants of the antihypertensive response and adverse metabolic responses (e.g. changes in glucose, triglycerides and uric acid). The proposed research is significant because genetically-targeted antihypertensive therapy could lead to dramatically higher response rates and fewer adverse effects than the usual trial-and-error approach. This would likely lead to higher rates of HTN control, less need for polypharmacy, reduced health care costs, and improved outcomes.

Conditions

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Hypertension

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Metoprolol + Chlorthalidone

Study participants in this group had their current hypertension treatment withdrawn, baseline labs drawn and hypertension documented. Participants were initiated on metoprolol tartrate 50 mg twice daily for two weeks, followed by dose titration to 100 mg twice daily for six additional weeks if blood pressure (BP) \> 120/70 mmHg. BP measures were again recorded. Participants entered a washout where metoprolol was titrated, then discontinued, and the patient's hypertension was re-established. After another set of identical baseline labs, study participants were initiated on chlorthalidone 25 mg four days per week (Monday, Wednesday, Thursday, Saturday) 15 mg daily for two weeks, followed by 25 mg daily for an additional six weeks.

Group Type EXPERIMENTAL

Metoprolol

Intervention Type DRUG

Metoprolol 50 mg twice daily titrated to 100 mg twice daily

Note: due to discontinuation of the manufacture of chlorthalidone 15 mg, effective Jan 1, 2013; the starting dose of chlorthalidone will be 25 mg 4 times per week (Mon, Wed, Thur, Sat) with subsequent titration to 25 mg daily.

Chlorthalidone

Intervention Type DRUG

Chlorthalidone 25 mg 4 times per week titrated to 25 mg daily

Interventions

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Metoprolol

Metoprolol 50 mg twice daily titrated to 100 mg twice daily

Note: due to discontinuation of the manufacture of chlorthalidone 15 mg, effective Jan 1, 2013; the starting dose of chlorthalidone will be 25 mg 4 times per week (Mon, Wed, Thur, Sat) with subsequent titration to 25 mg daily.

Intervention Type DRUG

Chlorthalidone

Chlorthalidone 25 mg 4 times per week titrated to 25 mg daily

Intervention Type DRUG

Other Intervention Names

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Lopressor Toprol XL Thalitone

Eligibility Criteria

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Inclusion Criteria

* An average seated home diastolic blood pressure (DBP) \> 85 mmHg and \< 110 mmHg and home systolic blood pressure (SBP) \< 180 mmHg.
* Subjects must also have an average seated (\> 5 minutes) clinic DBP between 90 mmHg and 110 mmHg and SBP \< 180 mmHg

Exclusion Criteria

* Secondary forms of hypertension (HTN) (including sleep apnea)
* Isolated systolic HTN
* Other diseases requiring treatment with BP lowering medications
* Heart rate \< 55 beats/min (for metoprolol only)
* Known cardiovascular disease (including history of angina pectoris, heart failure, presence of a cardiac pacemaker, history of myocardial infarction or revascularization procedure, or cerebrovascular disease, including stroke and TIA)
* Diabetes mellitus (Type 1 or 2)
* Renal insufficiency (serum creatinine \> 1.5 in men or 1.4 in women)
* Primary renal disease
* Pregnancy or lactation
* Liver enzymes \> 2.5 upper limits of normal
* Current treatment with NSAIDS, cyclooxygenase-2 (COX2) inhibitors, oral contraceptives or estrogen.

Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No