Management of Uncontrolled Hypertension: Ambulatory Blood Pressure Monitoring and Subsequent Modification of Therapy or Shifting Anti-hypertensive Medication to Night-time Dosing
Phase: NA
Conditions: Hypertension
Sponsor: University of Florida

 
 
 
 
 
 
Management of Uncontrolled Hypertension (HTN) 
 
NCT02922023 
 
10/26/2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Protocol 
 
1. Title: 
 
Management of Uncontrolled Hypertension: Ambulatory Blood Pressure Monitoring and 
Subsequent Modification of Therapy or Shifting Anti-hypertensive Medication to Night-
time Dosing 
 
2. Investigators: 
 
Principal Investigator: 
 
Katherine Vogel Anderson, Pharm.D. 
Clinical Assistant Professor  
Department of Pharmacotherapy and Translational Research 
 
Sub-Investigators: 
 
Kimberly Atkinson 
 
 
Resident Pharmacist, Pharm.D.  
 
 
UF College of Pharmacy 
 
 
 
Ryan Nall, M.D. 
 
 
Internal Medicine Physician 
 
 
UF Health Internal Medicine – Medical Plaza 
 
3. Abstract: 
 
Ambulatory Blood Pressure Monitoring (ABPM) and its role in clinical practice continues 
to evolve. ABPM allows providers to obtain blood pressure readings over a 24hour 
period, to assess blood pressure at night to determine “dipping” status, and to evaluate 
the efficacy of anti-hypertensive therapy. By utilizing ABPM in uncontrolled 
hypertension patients in clinical practice, modifications in drug therapy can be based on 
a more comprehensive and accurate depiction of the patient’s overall blood pressure 
control throughout the day. Although, theoretically, an assessment of the 24-hour blood 
pressure of a patient prior to adjusting drug therapy should yield better blood pressure 
control, we would like to carry out a pilot study to investigate whether the modifications 
in therapy based on ABPM and the resulting impact on blood pressure control would be 
substantially different from simply switching the dosing of medication to night-time.  
 
In this study, we will compare chronotherapy to ABPM. Data collected will include 
hypertension drug therapy regimen prior to and during the study, timing of medication 
administration, and dose, along with the patient’s office blood pressure values prior to 
study and one month after modification in therapy. This will enable us to explore 

whether it is a practical endeavor to implement ABPM as a routine process for all 
uncontrolled hypertension patients or whether ABPM does not seem to provide 
considerable value over shifting the timing of drug administration.  
 
4. Background: 
 
Hypertension affects approximately 29% of the US adult population, which equates to 
roughly 72 million people.1 Management of hypertension is of major importance 
because it is a key risk factor for heart failure, stroke, myocardial infarction, and 
cardiovascular disease. Another factor that has been found to correlate with the 
occurrence of complications in hypertension patients is dipping status. Dipping status 
refers to whether or not a patient’s blood pressure decreases during sleep. In 
normotensive patients, a dip in blood pressure of around 10% of the daytime blood 
pressure values is seen during sleep.2 The absence of dipping in blood pressure has been 
correlated with target organ damage and is associated with pseudo-resistant 
hypertension.3 Without access to night-time blood pressure readings, patients may be 
falsely diagnosed with resistant hypertension resulting in the unnecessary addition of 
medications. 
 
Ambulatory Blood Pressure Monitoring (ABPM) has garnered substantial scientific 
interest for its potential role in the diagnosis, management, and treatment of 
hypertension. Compelling indications for use of ABPM include identification of white-
coat hypertension, masked hypertension, and abnormal 24-hour blood pressure 
patterns. In addition, ABPM may be used to assess blood pressure treatment through 
evaluation of 24-hour blood pressure control and, by extension, identifying truly 
resistant hypertension patients.4  
 
ABPM is primarily used to diagnose white coat hypertension, however, ABPM may be 
used to assess efficacy of blood pressure treatment by evaluating the patient’s blood 
pressure control over a 24-hour period.5 The capability to provide night-time readings 
during sleep sets it apart from office blood pressure readings and home blood pressure 
readings, and it provides information for the determination of dipping status. Non-
dipping status has been associated with target organ damage including left ventricular 
hypertrophy, microalbuminuria, cerebrovascular disease, congestive heart failure, 
vascular dementia, stroke, and myocardial infarction.6 The frequency of non-dipper 
patterns tends to be higher in hypertension that is secondary to specific medical 
conditions such as chronic renal failure, diabetes, and autonomic nervous system 
dysfunction than in uncomplicated primary hypertension. A study also showed that the 
percentage of patients that ingest all their antihypertensive medications in the morning 
was significantly greater in non-dippers than the dippers suggesting that non-dipping 
among treated patients is partly due to lack of 24-hour therapeutic coverage when 
administered in the morning.9  
 
2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ ASH/ASPC/NMA/PCNA Guideline for the 
Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults 

stages hypertension as Stage 1 with pressure. Adults between the ages of 18 and 59 
years old or any adult with diabetes or chronic kidney disease are considered 
hypertensive with three consecutive blood pressure readings above 140/90 mmHg.7 
Resistant hypertension is defined as blood pressure that remains above the goal of 
130/80 mmHg despite the use of three anti-hypertensive agents at optimal doses 
including a diuretic, if possible, or blood pressure that is controlled with the use of four 
or more antihypertensive drugs.8 Although non-adherence is a common contributing 
factor to pseudo-resistant hypertension, it remains difficult to apply a simple, 
inexpensive, and reliable method in the clinical setting to quantify this factor when 
investigating potential causes for resistant hypertension.8  Additionally, seemingly 
resistant hypertension may be related to  inadequate night-time blood pressure control 
leading to elevated blood pressures during sleep as well as a higher-than-normal 
morning rise/spike upon awakening.6 
 
Chronotherapy is the purposeful timing of medications to synchronize drug 
concentrations with established circadian rhythms in an effort to enhance treatment 
outcomes and prevent adverse effects.6 Chronotherapy of anti-hypertensive 
medications has been used to attenuate morning rise of systolic and diastolic blood 
pressure, normalize elevated daytime, nighttime, and 24-hour blood pressure means, 
and convert abnormal 24-hour blood pressure profiles to normal dipping patterns.  
Tailoring medication levels in close synchrony with known and expected day-night 
patterns in both systolic and diastolic blood pressure can optimize the drug’s effects.9 
Given that optimal anti-hypertensive drug therapy may be dependent on circadian 
rhythms, dipping status, and individual 24-hour blood pressure patterns, along with the 
fact that ABPM serves as one of the only ways to easily evaluate a patient’s blood 
pressure patterns throughout the day and night, we are interested in investigating 
whether ABPM is  beneficial  in clinical practice. 
 
There are potential risks for dosing antihypertensive medications at bedtime in patients 
with visual field deterioration. A study which investigated 24-hour ABPM in patients 
with anterior ischemic optic neuropathy (AION), glaucoma, and other optic nerve head 
disorders have shown a 26% reduction in systolic blood pressure and 33% reduction in 
diastolic blood pressure at night.12 Patients with a progressive visual field deterioration 
had significantly greater mean decreases in systolic blood pressure from daytime 
readings (46.8 ± 2.5 mmHg) compared to those without deterioration (35.0 ± 3.1 
mmHg).12 Based on these and other studies, it was hypothesized that nocturnal 
hypotension may lead to ischemia of the anterior ciliary artery and reduce optic nerve 
head blood flow below a crucial level in certain vulnerable patients triggering the 
precipitation of AION and blindness.13 Therefore, patients with visual field deterioration 
should be excluded from the study to prevent the possibility of developing AION.   
 
Clinical application of ABPM may lead providers to add a new drug if the patient is a 
dipper or shift the dosing of an existing medication to night-time, or add a dose of an 
existing medication to bedtime. However, it is also possible that providers could simply 

move a medication to bedtime dosing, without relying on ABPM. Given that the initial 
cost associated with purchasing ABPM equipment ($2500-$5000) and software ($2000-
$3000)11 is not inconsequential, we propose this pilot study to determine whether 
ABPM in clinical practice is an investment that results in significant difference in blood 
pressure control when compared with chronotherapy. 
 
5. Specific Aim:  
 
We propose to conduct a pilot study to determine whether the incorporation of 
Ambulatory Blood Pressure Monitoring (ABPM) as routine procedure in clinic for 
uncontrolled hypertension influences how anti-hypertensive drug therapy is modified or 
if simply shifting the dosing of anti-hypertensive medications to night time achieves 
similar results. We will enroll 20 participants with uncontrolled hypertension, who are 
prescribed 3 anti-hypertensive medications. All twenty patients will undergo 24-hour 
blood pressure monitoring with ABPM at baseline and one month after change in 
therapy has been initiated; ten of the patients will be randomized to receive a shift in 
dosing schedule of anti-hypertensive medication to night-time without utilizing their 
ABPM results while the remaining ten will receive modifications in therapy based on 
their ABPM results and dipping status. The results of this study will assist in assessing 
the feasibility and benefits of the incorporation of ABPM into the routine management 
of hypertension.   
 
6. Research Plan:  
 
Patient eligibility 
 
Inclusion criteria 
1. Age ≥ 18 years  
2. Blood pressure of >130/80 mmHg  
3. Currently receiving 3 anti-hypertensive agents, one of which is a diuretic, for at 
least six weeks 
 
Exclusion criteria 
 
1. Vulnerable populations 
a. Pregnant women 
b. Prisoners 
c. Cognitively impaired persons 
d. Economically and/or educationally disadvantaged 
e. Human fetuses and neonates 
f. Patients who work night-shift 
g. Children 
h.  Conditions with visual field deterioration (Anterior Ischemic Optic 
Neuropathy, Glaucoma, Optic Nerve Disorders) 
 

Our target population is patients with uncontrolled hypertension. This study will recruit 
patients from the existing patient population assigned to a physician at the UF Health 
Internal Medicine Clinic at the Medical Plaza or enrolled in the Internal Medicine 
Interdisciplinary Hypertension Clinic. Patients that qualify/are eligible for the study will 
be identified by running a report through EPIC with the inclusion criteria. Either Dr. 
Vogel Anderson, or Kimberly Atkinson will obtain informed consent from eligible 
patients to enroll in the study. The informed consent form will summarize the consent 
discussion. Subjects, parents, or authorized representatives will be given the 
opportunity to consider and discuss the consent with family members and/or someone 
knowledgeable about the protocol.  We have changed the exclusion criteria from 
receiving three anti-hypertensive agents for at least three months to receiving three 
anti-hypertensive agents for at least six weeks to broaden our target population. 
Ambulatory Blood Pressure Monitoring is recommended in the 2017 ACC/AHA 
Guidelines for patients with resistant hypertension which is defined as having elevated 
blood pressure while being on 3 or more anti-hypertensive agents, with one being a 
diuretic, however, a timeframe for how long the patient is on the medications before 
qualifying as resistant hypertension is not defined.7 We chose six weeks to more closely 
align with the timeframe needed to see the true effect of a medication on the change in 
blood pressure.  
 
A total of twenty patients will be recruited and enrolled in this study. All twenty patients 
will wear the Spacelabs Ambulatory Blood Pressure Monitor Model No. 90207 for 24 
hours a total of two times – at baseline and following one month of the patient 
receiving their change in drug therapy. The randomization process to assign patients to 
either the group receiving chronotherapy or the group receiving therapy changes based 
on ABPM will be determined by placing strips of paper with the unique patient codes 
into an envelope and picking out numbers. One group will receive a shift in the timing of 
one of their antihypertensive medications to nighttime dosing without consulting their 
ABPM results. The other group will receive a modification in their antihypertensive 
medication regimen based on their ABPM results; modification in therapy would entail a 
shift in dosing of an existing blood pressure medication to nighttime for non-dippers 
while dippers would receive a change in regimen (change in strength of medication, 
addition of new medication, etc.) selected according to normal standard of care 
management of hypertension. Any specific changes to medication regimen outside of 
altering the timing of dose administration is not dictated by this study and will be based 
on usual process of treating uncontrolled hypertension patients and clinical expertise of 
the primary care physician. All subjects will be instructed on the operation of the ABPM 
and properly fitted with the monitor. Prior to leaving the office, they will undergo a 
minimum of one blood pressure reading to ensure adequate functioning of the monitor. 
They will also be given an information sheet detailing what to expect while using the 
ABPM as well as a diary to record the time of their meals, their medication 
administration, bedtime, time of awakening, any symptoms if they occur, and any 
period of stress or mood-altering activity that may affect the blood pressure reading. 
Patients will return the following day after wearing the monitor for 24 hours so that the 

data can be collected, and based on the group to which the patient was assigned, drug 
therapy may be modified according to the analysis of the ABPM results and their diary 
of activity. Requirements for a satisfactory ABPM involves having a minimum of 20 valid 
daytime measurements, a minimum of 7 measurements while asleep, and at least 70% 
of the measurements obtained at least every 30 minutes or more frequently throughout 
the 24-hour period.4  
 
Follow-up will occur for both treatment groups after one month of initiating their 
modified anti-hypertensive regimen to see how changes in drug therapy impact their 
blood pressure control. Patients will arrange for their follow-up 24-hour ABPM 
screening. The procedure from the first ABPM screening will be repeated, and the 
patient will return the following day to remove the monitor, return their ABPM diary, 
and submit their ABPM results for analysis. 
 

 
Chart 1: Flow chart demonstrating process for conducting the study 
 
Aside from patients receiving ABPM, all patients will receive standard care in managing 
their hypertension involving hypertension follow-up appointments and adjustments in 
therapy to achieve adequate blood pressure control. For those patients who are in the 
group whose changes in therapy will be determined after evaluating their ABPM results, 
patients found to be dippers and would not benefit from the switch in dosing to 
nighttime will receive changes in therapy as would be expected in clinic as standard care 
if a dose increase/medication change is warranted. Clinical data will be obtained from 
standard blood pressure monitoring equipment provided by the clinic. Therefore, this 
study will not result in additional charges associated with the treatment and care of the 
patient. 
 

Data collection will include age, sex, race, height, weight, comorbidities (Diabetes 
Mellitus, hyperlipidemia, history of stroke, transient ischemic attack, myocardial 
infarction, etc.), antihypertensive therapies including dosing schedule at baseline as well 
as after modification from receiving either treatment option, complete medication 
history including over-the-counter and herbal medications, whether or not the patient 
uses a home blood pressure monitor (yes or no), lifestyle history including caffeine and 
alcohol intake and tobacco use, number of years since HTN diagnosis, whether or not 
patient was at blood pressure goal at the follow-up visit at one month after initiating 
change in therapy (yes or no), and the blood pressure readings from the ambulatory 
blood pressure monitor at baseline and one month post initiation of change in drug 
therapy. Data will be obtained through EPIC, including the patient-recorded data such as 
the diary of activity during the 24 hours wearing the ABPM which will be scanned into 
EPIC. The results of the ABPM will be obtained from the ABPM software and may be 
scanned into EPIC for ease of access.    
 
Descriptive statistics, including REDCap (Research Electronic Data Capture) will be used 
to analyze patient data. Unique patient codes will randomly be assigned to each patient 
participating in the study through REDCap, and the patient code will serve as the 
identity of the patient throughout the study. The master list linking the patient codes to 
the specific patient names will be kept as a physical copy that will remain in a locked 
filing cabinet in HPNP Room 3313, and only the investigators will have access. The list 
will be shredded at the conclusion of the study. All electronic files containing clinical 
information will have PHI removed, and data will be stored on encrypted, password 
protected files accessed on a UF server. No information will be released to any person 
or agency without consent of the subject except as required by law.  
 
Analysis plan for initial questions: To determine whether there is a difference in 
achieving blood pressure goal by using ABPM or chronotherapy.   
 
Descriptive statistics will be carried out using paired t test (changes in  
blood pressure from baseline vs after 1 month of change in drug therapy for each 
patient) and Chi-square test or Fisher’s Exact Test (amount of subjects from each group 
that achieved blood pressure goal).  
 
For researchers other than those named on the protocol, use of the data and samples 
procured under this study will require approval from the PIs of this study in addition to 
the IRB. 
 
7. Possible Discomforts and Risks: 
 
Risk to the patient from participation in this study is minimal. Participants will not be 
subjected to processes beyond what is required for obtaining a satisfactory 24-hour 
blood pressure evaluation and required for routine monitoring of hypertension. Risks of 
using the ABPM are none. Slight discomfort may occur while wearing the ABPM device 
throughout the 24 hours as the device periodically inflates, and there may be modest 
sleep disturbances at the intervals when blood pressure readings are taken. Aside from 

the aforementioned, participants will not have any additional discomforts beyond those 
associated with routine management of their hypertension.   
 
8. Possible Benefits: 
 
Study subjects may experience benefits from participation in the study if modifications 
in therapy lead to blood pressure control and achieving patients’ blood pressure goals. 
The results of this study may help to improve anti-hypertensive drug therapy by tailoring 
and individualizing drug regimens based on patient blood pressure patterns. Results 
may lead to increased incorporation and use of ABPM in clinical practice and may help 
us improve how uncontrolled hypertension is treated and managed in clinic, thus 
providing possible advancements and modifications of protocol in clinic. Therefore, the 
potential information gained from this study outweighs the minimal risk associated with 
study participation. 
 
9. Data Safety Monitoring Plan: 
 
Based on assessments of the risk-to-benefit ratio, the risk level associated with the 
study is minimal. All risks have been described in the consent form.  
  
Monitoring for documentation of an adverse event, whether anticipated or 
unanticipated, is the responsibility of the principal investigator or co-investigators. 
Regarding safety monitoring, all adverse events spontaneously reported, elicited, or 
observed by the investigators will be recorded. All Serious Adverse Events, should they 
occur, whether study-related or expected, will be documented in REDCap and reported 
to the IRB within five (5) working days. 
 
In addition, the principal investigator will follow the reporting requirements for serious 
and unexpected adverse events outlined in the UF IRB Adverse Event Evaluation and 
Reporting Guide. All unanticipated, serious, fatal and/or life-threatening adverse events 
will be reported to the UF IRB. Aggregate reports of adverse events will be prepared on 
an annual basis or at the end of the study, whichever may occur earlier and forwarded 
to the IRB at annual review. 
  
Plan for data management:  Data collection for each subject will be recorded within 
REDCap. To protect the participant’s right of privacy, the master list linking study-
assigned patient codes to the patients’ personal identifiers will be stored in locked 
cabinets with limited access, and electronic files will be kept in secured database. A de-
identified dataset from the database using a patient identification number will then be 
shared with statistician for analysis. During the study, data will be analyzed as it 
becomes available by the PI and co-investigators. No early closure is planned because of 
the limited scope and projected low risk of the study. 
 
There is a prospect of direct benefit to individual subjects in that assessing ambulatory 
blood pressure monitoring results could lead to appropriate modifications in anti-
hypertensive drug regimens that may assist in improving blood pressure control.  
 

Nevertheless, in the absence of a direct benefit, the study may advance the fields by 
offering a better understanding of the capacity at which ABPM can be incorporated into 
routine clinical practice and standard management of hypertension.  
 
10. Conflict of Interest:  
 
There are no conflicts of interest involved with this study beyond the professional 
benefits from academic publication or presentation of research results. 
 
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