Pharmacogenomic Evaluation of Antihypertensive Responses

NCT00246519 | Completed Phase 4 Results DMC

• 1 other identifier: U01GM074492
• Study Type: interventional
• Target: 1,701
• Locations: 1 country
• Sites: 3

Brief Summary

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 only 34% 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, we 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.

Conditions

Hypertension

Keywords

hypertension; pharmacogenetics; pharmacogenomics; beta-blocker; atenolol; diuretic; hydrochlorothiazide; blood pressure; metabolic adverse effects

Outcome Measures

Primary Outcomes (1)

• Blood Pressure Response (Delta BP (After 18 Weeks of Medication - Baseline)).

  baseline to 18 weeks of treatment

Secondary Outcomes (1)

• Adverse Metabolic Responses

  9-18 weeks of treatment

Study Arms (2)

Atenolol

EXPERIMENTAL

atenolol 50 mg, then 100 mg if BP \< 120/70, then add HCTZ 12.5 mg if BP \< 120/70, then HCTZ 25 mg if BP \< 120/70

Drug: Atenolol

Hydrochlorothiazide (HCTZ)

EXPERIMENTAL

HCTZ 12.5 mg then HCTZ 25 mg if BP \< 120/70, then add atenolol 50 mg if BP \< 120/70, then atenolol 100 mg if BP \< 120/70.

Drug: Hydrochlorothiazide

Interventions

Hydrochlorothiazide DRUG

atenolol 50 or 100 mg hydrochlorothiazide 12.5 or 25 mg

Also known as: Aquazide H or HydroDIURIL or Microzide, Lopressor

Hydrochlorothiazide (HCTZ)

Atenolol DRUG

atenolol 50 mg, then 100 mg if BP \< 120/70, then add HCTZ 12.5 mg if BP \< 120/70, then HCTZ 25 mg if BP \< 120/70

Also known as: Lopressor, Aquazide H or HydroDIURIL or Microzide

Atenolol

Eligibility Criteria

• Age: 17 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• An average seated home diastolic blood pressure (DBP) \> 85 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

You may not qualify if:

• secondary forms of HTN, patients currently treated with three or more antihypertensive drugs, isolated systolic HTN, other diseases requiring treatment with BP lowering medications, heart rate \< 55 beats/min, 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.

Sponsors & Collaborators

• University of Florida: lead

Study Sites (3)

University of Florida Department of Community Health and Family Medicine

Gainesville, Florida, 32610, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Related Publications (30)

• Johnson JA, Boerwinkle E, Zineh I, Chapman AB, Bailey K, Cooper-DeHoff RM, Gums J, Curry RW, Gong Y, Beitelshees AL, Schwartz G, Turner ST. Pharmacogenomics of antihypertensive drugs: rationale and design of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study. Am Heart J. 2009 Mar;157(3):442-9. doi: 10.1016/j.ahj.2008.11.018.

  PMID: 19249413 RESULT

• Johnson JA, Gong Y, Bailey KR, Cooper-DeHoff RM, Chapman AB, Turner ST, Schwartz GL, Campbell K, Schmidt S, Beitelshees AL, Boerwinkle E, Gums JG. Hydrochlorothiazide and atenolol combination antihypertensive therapy: effects of drug initiation order. Clin Pharmacol Ther. 2009 Nov;86(5):533-9. doi: 10.1038/clpt.2009.101. Epub 2009 Jul 1.

  PMID: 19571804 RESULT

• Smith SM, Anderson SD, Wen S, Gong Y, Turner ST, Cooper-Dehoff RM, Schwartz GL, Bailey K, Chapman A, Hall KL, Feng H, Boerwinkle E, Johnson JA, Gums JG. Lack of correlation between thiazide-induced hyperglycemia and hypokalemia: subgroup analysis of results from the pharmacogenomic evaluation of antihypertensive responses (PEAR) study. Pharmacotherapy. 2009 Oct;29(10):1157-65. doi: 10.1592/phco.29.10.1157.

  PMID: 19792989 RESULT

• Cooper-DeHoff RM, Wen S, Beitelshees AL, Zineh I, Gums JG, Turner ST, Gong Y, Hall K, Parekh V, Chapman AB, Boerwinkle E, Johnson JA. Impact of abdominal obesity on incidence of adverse metabolic effects associated with antihypertensive medications. Hypertension. 2010 Jan;55(1):61-8. doi: 10.1161/HYPERTENSIONAHA.109.139592. Epub 2009 Nov 16.

  PMID: 19917874 RESULT

• Beitelshees AL, Gong Y, Bailey KR, Turner ST, Chapman AB, Schwartz GL, Gums JG, Boerwinkle E, Johnson JA. Comparison of office, ambulatory, and home blood pressure antihypertensive response to atenolol and hydrochlorthiazide. J Clin Hypertens (Greenwich). 2010 Jan;12(1):14-21. doi: 10.1111/j.1751-7176.2009.00185.x.

  PMID: 20047624 RESULT

• Duarte JD, Lobmeyer MT, Wang Z, Chapman AB, Gums JG, Langaee TY, Boerwinkle E, Turner ST, Johnson JA. Lack of association between polymorphisms in STK39, a putative thiazide response gene, and blood pressure response to hydrochlorothiazide. Pharmacogenet Genomics. 2010 Aug;20(8):516-9. doi: 10.1097/FPC.0b013e32833b5958.

  PMID: 20555294 RESULT

• Smith SM, Gong Y, Turner ST, Cooper-DeHoff RM, Beitelshees AL, Chapman AB, Boerwinkle E, Bailey K, Johnson JA, Gums JG. Blood pressure responses and metabolic effects of hydrochlorothiazide and atenolol. Am J Hypertens. 2012 Mar;25(3):359-65. doi: 10.1038/ajh.2011.215. Epub 2011 Nov 17.

  PMID: 22089105 RESULT

• Lobmeyer MT, Wang L, Zineh I, Turner ST, Gums JG, Chapman AB, Cooper-DeHoff RM, Beitelshees AL, Bailey KR, Boerwinkle E, Pepine CJ, Johnson JA. Polymorphisms in genes coding for GRK2 and GRK5 and response differences in antihypertensive-treated patients. Pharmacogenet Genomics. 2011 Jan;21(1):42-9. doi: 10.1097/FPC.0b013e328341e911.

  PMID: 21127457 RESULT

• Cooper-DeHoff RM, Gong Y, Handberg EM, Bavry AA, Denardo SJ, Bakris GL, Pepine CJ. Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. JAMA. 2010 Jul 7;304(1):61-8. doi: 10.1001/jama.2010.884.

  PMID: 20606150 RESULT

• Turner ST, Schwartz GL, Chapman AB, Beitelshees AL, Gums JG, Cooper-DeHoff RM, Boerwinkle E, Johnson JA, Bailey KR. Plasma renin activity predicts blood pressure responses to beta-blocker and thiazide diuretic as monotherapy and add-on therapy for hypertension. Am J Hypertens. 2010 Sep;23(9):1014-22. doi: 10.1038/ajh.2010.98. Epub 2010 Aug 19.

  PMID: 20725057 RESULT

• Wikoff WR, Frye RF, Zhu H, Gong Y, Boyle S, Churchill E, Cooper-Dehoff RM, Beitelshees AL, Chapman AB, Fiehn O, Johnson JA, Kaddurah-Daouk R; Pharmacometabolomics Research Network. Pharmacometabolomics reveals racial differences in response to atenolol treatment. PLoS One. 2013;8(3):e57639. doi: 10.1371/journal.pone.0057639. Epub 2013 Mar 11.

  PMID: 23536766 RESULT

• Del-Aguila JL, Beitelshees AL, Cooper-Dehoff RM, Chapman AB, Gums JG, Bailey K, Gong Y, Turner ST, Johnson JA, Boerwinkle E. Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.

  PMID: 23400010 RESULT

• McDonough CW, Burbage SE, Duarte JD, Gong Y, Langaee TY, Turner ST, Gums JG, Chapman AB, Bailey KR, Beitelshees AL, Boerwinkle E, Pepine CJ, Cooper-DeHoff RM, Johnson JA. Association of variants in NEDD4L with blood pressure response and adverse cardiovascular outcomes in hypertensive patients treated with thiazide diuretics. J Hypertens. 2013 Apr;31(4):698-704. doi: 10.1097/HJH.0b013e32835e2a71.

  PMID: 23353631 RESULT

• Gong Y, McDonough CW, Wang Z, Hou W, Cooper-DeHoff RM, Langaee TY, Beitelshees AL, Chapman AB, Gums JG, Bailey KR, Boerwinkle E, Turner ST, Johnson JA. Hypertension susceptibility loci and blood pressure response to antihypertensives: results from the pharmacogenomic evaluation of antihypertensive responses study. Circ Cardiovasc Genet. 2012 Dec;5(6):686-91. doi: 10.1161/CIRCGENETICS.112.964080. Epub 2012 Oct 19.

  PMID: 23087401 RESULT

• Vandell AG, Lobmeyer MT, Gawronski BE, Langaee TY, Gong Y, Gums JG, Beitelshees AL, Turner ST, Chapman AB, Cooper-DeHoff RM, Bailey KR, Boerwinkle E, Pepine CJ, Liggett SB, Johnson JA. G protein receptor kinase 4 polymorphisms: beta-blocker pharmacogenetics and treatment-related outcomes in hypertension. Hypertension. 2012 Oct;60(4):957-64. doi: 10.1161/HYPERTENSIONAHA.112.198721. Epub 2012 Sep 4.

  PMID: 22949529 RESULT

• Duarte JD, Zineh I, Burkley B, Gong Y, Langaee TY, Turner ST, Chapman AB, Boerwinkle E, Gums JG, Cooper-Dehoff RM, Beitelshees AL, Bailey KR, Fillingim RB, Kone BC, Johnson JA. Effects of genetic variation in H3K79 methylation regulatory genes on clinical blood pressure and blood pressure response to hydrochlorothiazide. J Transl Med. 2012 Mar 22;10:56. doi: 10.1186/1479-5876-10-56.

  PMID: 22440088 RESULT

• Duarte JD, Turner ST, Tran B, Chapman AB, Bailey KR, Gong Y, Gums JG, Langaee TY, Beitelshees AL, Cooper-Dehoff RM, Boerwinkle E, Johnson JA. Association of chromosome 12 locus with antihypertensive response to hydrochlorothiazide may involve differential YEATS4 expression. Pharmacogenomics J. 2013 Jun;13(3):257-63. doi: 10.1038/tpj.2012.4. Epub 2012 Feb 21.

  PMID: 22350108 RESULT

• Mehanna M, McDonough CW, Smith SM, Gong Y, Gums JG, Chapman AB, Johnson JA, Cooper-DeHoff RM. Integrated metabolomics analysis reveals mechanistic insights into variability in blood pressure response to thiazide diuretics and beta blockers. Clin Transl Sci. 2024 May;17(5):e13816. doi: 10.1111/cts.13816.

  PMID: 38747311 DERIVED

• Chekka LMS, Tantawy M, Langaee T, Wang D, Renne R, Chapman AB, Gums JG, Boerwinkle E, Cooper-DeHoff RM, Johnson JA. Circulating microRNA Biomarkers of Thiazide Response in Hypertension. J Am Heart Assoc. 2024 Feb 20;13(4):e032433. doi: 10.1161/JAHA.123.032433. Epub 2024 Feb 14.

  PMID: 38353215 DERIVED

• Mehanna M, Wang Z, Gong Y, McDonough CW, Beitelshees AL, Gums JG, Chapman AB, Schwartz GL, Bailey KR, Johnson JA, Turner ST, Cooper-DeHoff RM. Plasma Renin Activity Is a Predictive Biomarker of Blood Pressure Response in European but not in African Americans With Uncomplicated Hypertension. Am J Hypertens. 2019 Jun 11;32(7):668-675. doi: 10.1093/ajh/hpz022.

  PMID: 30753254 DERIVED

• Sa ACC, Webb A, Gong Y, McDonough CW, Shahin MH, Datta S, Langaee TY, Turner ST, Beitelshees AL, Chapman AB, Boerwinkle E, Gums JG, Scherer SE, Cooper-DeHoff RM, Sadee W, Johnson JA. Blood pressure signature genes and blood pressure response to thiazide diuretics: results from the PEAR and PEAR-2 studies. BMC Med Genomics. 2018 Jun 20;11(1):55. doi: 10.1186/s12920-018-0370-x.

  PMID: 29925376 DERIVED

• McDonough CW, Magvanjav O, Sa ACC, El Rouby NM, Dave C, Deitchman AN, Kawaguchi-Suzuki M, Mei W, Shen Y, Singh RSP, Solayman M, Bailey KR, Boerwinkle E, Chapman AB, Gums JG, Webb A, Scherer SE, Sadee W, Turner ST, Cooper-DeHoff RM, Gong Y, Johnson JA. Genetic Variants Influencing Plasma Renin Activity in Hypertensive Patients From the PEAR Study (Pharmacogenomic Evaluation of Antihypertensive Responses). Circ Genom Precis Med. 2018 Apr;11(4):e001854. doi: 10.1161/CIRCGEN.117.001854.

  PMID: 29650764 DERIVED

• Singh S, McDonough CW, Gong Y, Alghamdi WA, Arwood MJ, Bargal SA, Dumeny L, Li WY, Mehanna M, Stockard B, Yang G, de Oliveira FA, Fredette NC, Shahin MH, Bailey KR, Beitelshees AL, Boerwinkle E, Chapman AB, Gums JG, Turner ST, Cooper-DeHoff RM, Johnson JA. Genome Wide Association Study Identifies the HMGCS2 Locus to be Associated With Chlorthalidone Induced Glucose Increase in Hypertensive Patients. J Am Heart Assoc. 2018 Mar 9;7(6):e007339. doi: 10.1161/JAHA.117.007339.

  PMID: 29523524 DERIVED

• Shahin MH, Conrado DJ, Gonzalez D, Gong Y, Lobmeyer MT, Beitelshees AL, Boerwinkle E, Gums JG, Chapman A, Turner ST, Cooper-DeHoff RM, Johnson JA. Genome-Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to beta-Blockers. J Am Heart Assoc. 2018 Feb 24;7(5):e006463. doi: 10.1161/JAHA.117.006463.

  PMID: 29478026 DERIVED

• Shahin MH, Gong Y, Frye RF, Rotroff DM, Beitelshees AL, Baillie RA, Chapman AB, Gums JG, Turner ST, Boerwinkle E, Motsinger-Reif A, Fiehn O, Cooper-DeHoff RM, Han X, Kaddurah-Daouk R, Johnson JA. Sphingolipid Metabolic Pathway Impacts Thiazide Diuretics Blood Pressure Response: Insights From Genomics, Metabolomics, and Lipidomics. J Am Heart Assoc. 2017 Dec 29;7(1):e006656. doi: 10.1161/JAHA.117.006656.

  PMID: 29288159 DERIVED

• Magvanjav O, Gong Y, McDonough CW, Chapman AB, Turner ST, Gums JG, Bailey KR, Boerwinkle E, Beitelshees AL, Tanaka T, Kubo M, Pepine CJ, Cooper-DeHoff RM, Johnson JA. Genetic Variants Associated With Uncontrolled Blood Pressure on Thiazide Diuretic/beta-Blocker Combination Therapy in the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) and INVEST (International Verapamil-SR Trandolapril Study) Trials. J Am Heart Assoc. 2017 Nov 2;6(11):e006522. doi: 10.1161/JAHA.117.006522.

  PMID: 29097388 DERIVED

• Shahin MH, Sa AC, Webb A, Gong Y, Langaee T, McDonough CW, Riva A, Beitleshees AL, Chapman AB, Gums JG, Turner ST, Boerwinkle E, Scherer SE, Sadee W, Cooper-DeHoff RM, Johnson JA. Genome-Wide Prioritization and Transcriptomics Reveal Novel Signatures Associated With Thiazide Diuretics Blood Pressure Response. Circ Cardiovasc Genet. 2017 Jan;10(1):e001404. doi: 10.1161/CIRCGENETICS.116.001404.

  PMID: 28115488 DERIVED

• Moore MJ, Gong Y, Hou W, Hall K, Schmidt SO, Curry RW Jr, Beitelshees AL, Chapman A, Turner ST, Schwartz GL, Bailey K, Boerwinkle E, Gums JG, Cooper-DeHoff RM, Johnson JA. Predictors for glucose change in hypertensive participants following short-term treatment with atenolol or hydrochlorothiazide. Pharmacotherapy. 2014 Nov;34(11):1132-40. doi: 10.1002/phar.1483. Epub 2014 Sep 9.

  PMID: 25202885 DERIVED

• Cooper-Dehoff RM, Hou W, Weng L, Baillie RA, Beitelshees AL, Gong Y, Shahin MH, Turner ST, Chapman A, Gums JG, Boyle SH, Zhu H, Wikoff WR, Boerwinkle E, Fiehn O, Frye RF, Kaddurah-Daouk R, Johnson JA. Is diabetes mellitus-linked amino acid signature associated with beta-blocker-induced impaired fasting glucose? Circ Cardiovasc Genet. 2014 Apr;7(2):199-205. doi: 10.1161/CIRCGENETICS.113.000421. Epub 2014 Mar 13.

  PMID: 24627569 DERIVED

• Chapman AB, Cotsonis G, Parekh V, Schwartz GL, Gong Y, Bailey KR, Turner ST, Gums JG, Beitelshees AL, Cooper-DeHoff R, Boerwinkle E, Johnson JA. Night blood pressure responses to atenolol and hydrochlorothiazide in black and white patients with essential hypertension. Am J Hypertens. 2014 Apr;27(4):546-54. doi: 10.1093/ajh/hpt124. Epub 2013 Jul 25.

  PMID: 23886594 DERIVED

Related Links

• PEAR website

MeSH Terms

Conditions

Hypertension

Interventions

Hydrochlorothiazide; Metoprolol; Atenolol

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Chlorothiazide; Benzothiadiazines; Sulfonamides; Sulfones; Sulfur Compounds; Organic Chemicals; Thiazides; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Propanols; Amines

Limitations and Caveats

The trial has limited number of hypertensive patients of African ancestry, therefore power is limited to those patients.

Results Point of Contact

• Title: Julie A. Johnson
• Organization: University of Florida

johnson@cop.ufl.edu

352-273-6007

Study Officials

• Julie A Johnson, PharmD

  University of Florida

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 27, 2005
• First Posted: October 31, 2005
• Study Start: October 1, 2005
• Primary Completion: December 1, 2010
• Study Completion: December 1, 2010
• Last Updated: May 7, 2018
• Results First Posted: July 10, 2013

Record last verified: 2018-04

Locations

US (3)