Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR)

This is a prospective, multicenter, randomized, open-label, parallel-group study to evaluate pharmacogenomic responses to antihypertensives. The primary aim of this study is to identify the genetic determinants of antihypertensive and adverse metabolic responses focused on two preferred and pharmacodynamically contrasting drugs, a beta-blocker (atenolol) and a thiazide diuretic (HCTZ) given initially as monotherapy, and subsequently in combination, to 768 individuals with uncomplicated hypertension. This includes assessment of genetic associations with: antihypertensive responses to monotherapy, addition of a second drug to monotherapy, and combination therapy; and adverse metabolic responses to mono and combination therapy. High quality phenotype data, including both home and ambulatory measures of blood pressure response, and lipid and insulin sensitivity measures of adverse metabolic responses were collected. DNA samples were plated into 96-well plates and included a 2% sample replication for QC and a Caucasian parent-child CEPH trio from the HapMap project to check for Mendelian transmission of alleles. Genotypes were determined with the Illumina HumanOmni1-Quad and HumanCVD BeadChip.

• Study Weblinks:
  • Pharmacogenomic Evaluation of Antihypertensive Responses
• Study Design:
  • Prospective Longitudinal Cohort
• Study Type:
  • Prospective
  • Randomized
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 230
• Subject Sample Telemetry Report (SSTR)

• BioSample

Exclusion criteria will include: secondary forms of HTN (including sleep apnea), patients currently treated with three or more antihypertensive drugs, or patients taking antihypertensive drugs with properly measured clinic SBP > 170 mmHg, isolated systolic HTN, other diseases requiring treatment with BP lowering medications, heart rate < 55 beats/min (in the absence of beta-blocker therapy), 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 as a serum creatinine > 1.5 mg/dl in males and 1.4 mg/dl in females), primary renal disease, pregnancy or lactation, or a history of Raynaud's syndrome. To avoid confounding based on their potential effects on blood pressure, individuals who take chronic (i.e. daily) nonsteroidal antiinflammatory drugs, COX-2 inhibitors, oral contraceptives or estrogen replacement products will be excluded. Additionally, patients with alcoholism or recreational drug use will be excluded due to concerns about the ability to comply with the study requirements. For any subjects where there is suspicion of secondary HTN (especially children and young adults), it must be ruled out as part of the patient's usual medical care before they could be considered for inclusion in the study. Subjects with asthma or COPD can be included at the discretion of the treating physician. The presence of exclusion criteria will be ascertained through history, physical examination and routine laboratory analysis (i.e., basic chemistry profile, urinalysis, and urine pregnancy test in women of child-bearing potential). The majority of these exclusion criteria are in place for safety reasons. They lead to exclusion of those subjects in whom withdrawal of therapy would be considered potentially unsafe (and in many cases unethical), those in whom beta-blocker or diuretic do not represent the appropriate first-line treatment of HTN, and those in whom treatment with a beta-blocker or diuretic is contraindicated, or relatively contraindicated.

Patients who do not meet any exclusion criteria will be further screened for inclusion, which will be based on meeting criteria for untreated home and clinic BP, described below. Subjects will undergo extensive training by research personnel on the use of the home BP monitor, and will be provided a monitor and appropriately sized cuff to take home. Antihypertensive medications will have them discontinued (or tapered if receiving a delta-blocker or clonidine). Regular home and clinic BP monitoring will occur during this time. After patients have been untreated for at least two weeks, they will be screened for study enrollment, based on both home BP (HBP) and clinic BP (CBP) data. To enter the randomization phase of the study, subjects must record HBP twice daily (morning and evening) in triplicate for at least five days, over a period of no greater than seven days. (Note: the home BP monitors to be used in this study will automatically take triplicate readings). They must have an average seated home DBP > 85 mmHg and home SBP < 180 mmHg. Subjects must also have an average seated (> 5 minutes) clinic DBP between 90 mmHg and SBP E 180 mmHg. Additionally, patients will be excluded if both home and clinic DBP are ≥ 110 mmHg. Subjects will be excluded for a sustained clinic SBP > 180 mmHg at a single clinic visit, with sustained defined as a minimum of three BP readings taken over a minimum of one hour. Thus subjects with be enrolled based on diastolic HTN, with or without systolic HTN. A summary of the BP inclusion/exclusion requirements follows:

Eligibility phase/baseline studies (Activity 2/3):

• Inclusion: Weekly average home DBP must be > 85 mmHg AND clinic DBP must be > 90 mmHg

• Exclusion: patient should be terminated from study if home OR clinic SBP > 180 mmHg OR home AND clinic DBP ≥ 110 mmHg.

Both HBP and CBP will be used to determine eligibility for enrollment in the study for several reasons. Home BP is used for inclusion to help eliminate subjects who have white coat HTN, but not essential HTN, while CBP values are used because usual clinical practice at present is to rely on clinic BP, and by including CBP values for enrollment and titration, the study will have greater external validity. The home BP levels used for inclusion (>85 mmHg) are lower than those for the clinic BP (>90 mmHg) because home BP is lower than clinic BP in the vast majority of subjects (see Table 1 for examples). This cut point for HBP was selected because a home BP > 135/85 mmHg is recommended in European Society of HTN guidelines as the current best estimate as the cutoff for an abnormal home BP.

Study Start Date:
October 2005
Study Completion Date:
December 2010
Primary Completion Date:
December 2010 (Final data collection date for primary outcome measure)

Data release will be in done in versions. The first version will be uploaded September 1, 2013 and will include the phenotype and genotype data for Caucasians and African Americans who were randomized to HCTZ first. The second version of the data will be uploaded March 1, 2014 will include all data for all subjects from both treatment arms.

• Primary Phenotype: Hypertension
• Metabolic Diseases

• Principal Investigator
  • Julie A. Johnson. University of Florida, Gainesville, FL USA.
• Funding Source
  • U01 GM074492. National Institutes of Health, Bethesda, MD, USA.