The Effects of Medication Induced Blood Pressure Reduction on Cerebral Hemodynamics in Hypertensive Frail Elderly (BLUEBERRY)

Rationale: Systolic hypertension represents the leading risk for burden of disease among older adults (age >70 years), with an increasing prevalence due to the increase in lifespan. Antihypertensive drug treatment (AHT) is beneficial in fit (non-frail) older adults, with substantial (≈40 %) risk reductions for cardiovascular events and mortality. Scarce evidence exists on the risks of adverse effects related to AHT. It has been suggested in medical literature that AHT in frail elderly might cause cerebral hypoperfusion and/or orthostatic hypotension. Therefore, current guidelines advise clinicians to be more cautious regarding treatment targets in this population. However, the evidence for these adverse effects is limited to observational and cross-sectional data and opinion pieces. In contrast to the suggestion of potential adverse effects of AHT in elderly, recent experimental data and secondary analyses of clinical trials do not provide support for this statement. However, evidence in frail older patients remains scarce. Studies that directly examine the safety of AHT with regard to cerebral hemodynamics and orthostatic tolerance in frail elderly are needed to inform potential changes in current treatment guidelines and prevent undertreatment of hypertension in frail older patients.

Objective: To examine the impact of medication induced systolic BP (SBP) reductions ≥10 mmHg, while reaching a treatment target of ≤140 mmHg, on cerebral blood flow (CBF) in frail elderly with untreated or uncontrolled systolic hypertension at baseline. We hypothesise that these blood pressure lowering targets (which are consistent with clinical guidelines for non-frail older patients) are not accompanied by detrimental reductions in CBF (i.e. >10% from baseline).

Study design: An explorative observational study will be performed to examine the effects of medication induced SBP reductions ≥10 mmHg to office SBP ≤140 mmHg on CBF in frail elderly with untreated or uncontrolled hypertension. Participants will be treated as in usual patient care for older adults with hypertension. Participants will undergo one baseline assessment before exposure to (additional) AHT, followed by in duplo follow-up assessments 6-10 weeks after the start of AHT. The in duplo follow-up evaluations will be performed on separate days within 2 weeks while continuing treatment.

Study population: Twelve frail (Clinical Frailty Scale 4-7) elderly (age ≥70 years) with untreated or uncontrolled systolic hypertension (office SBP ≥150 mmHg) that will be subjected to (additional) AHT as part of regular care.

Main study parameters/endpoints: The change in resting CBF from baseline to follow-up (i.e. the average of the in duplo follow-up assessments). Secondary outcomes relate to cerebrovascular autoregulation (CA) and orthostatic tolerance.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Subjects will be subjected to AHT, essentially identical to what is considered 'guideline care', while their wellbeing will be monitored closely. Since all study procedures and used measurement techniques are non-invasive, the nature and extent of burden and risks associated with participation and measurements are negligible.

Study Overview

• Status: Recruiting
• Conditions: Hypertension; Frailty; Orthostatic Hypotension; Orthostatic Intolerance; Cerebral Hypoperfusion; Old Age; Dementia
• Intervention / Treatment: Drug: Antihypertensive Agents

• Study Type: Observational
• Enrollment (Estimated): 15

Contacts and Locations

• Study Contact: Name: Ralf W Weijs, MSc; Phone Number: +31653421561; Email: ralf.weijs@radboudumc.nl
• Study Contact Backup: Name: Jurgen A Claassen, MD, PhD; Phone Number: +31243697059; Email: jurgen.claassen@radboudumc.nl

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Recruiting
      • Radboudumc
      • Contact: Ralf W Weijs, MSc; Phone Number: +31243610152; Email: ralf.weijs@radboudumc.nl
      • Contact: Jurgen A Claassen, MD, PhD; Email: jurgen.claassen@radboudumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 70 years and older (Older Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Hypertensive frail older adults

Description

Inclusion Criteria:

• Age ≥70 years.
• Clinical Frailty Scale ≥4 and ≤7.

• Diagnosis of:

  • Untreated systolic hypertension, i.e. unattended office SBP ≥150 mmHg without AHT, or;
  • Uncontrolled systolic hypertension, i.e. unattended office SBP ≥150 mmHg despite AHT.

• Will be starting (untreated) or adding (uncontrolled) AHT in the near future for (further) reducing SBP by ≥10 mmHg while reaching a treatment target of unattended office SBP

  ≤140 mmHg, while keeping unattended office diastolic blood pressure ≥70 mmHg, with the indication of primary or secondary prevention of vascular events, judged by the treating physician (geriatrician or primary care physician)

• Able to understand and perform study related procedures.

Exclusion Criteria:

• Unable to provide signed and dated informed consent form.
• Mentally incompetent subjects (e.g. due to dementia) as assessed by a physician.
• Currently enrolled in another interventional study targeting either BP and/or CBF.
• Cardiovascular event within the past 3 months.
• Estimated glomerular filtration rate (eGFR) <40 ml/min.
• Known secondary cause of hypertension that causes safety concerns.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in MCAv across follow-up	The primary study parameter is the relative change in CBF from baseline to follow-up (i.e. the average of the in duplo follow-up assessments), measured as the mean bilateral CBF velocity in the MCA (in cm/s).	6-8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in cerebral autoregulation and orthostatic tolerance	The relative and absolute changes in measures of CA (i.e. dCA and BRS) and OT from baseline to follow-up. Regarding OT, it will also be evaluated whether the incidence of orthostatic hypotension differs between baseline and follow-up assessments.	6-8 weeks

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Jurgen A Claassen, MD, PhD, Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2022
• Primary Completion (Actual): July 18, 2023
• Study Completion (Estimated): September 1, 2023

Study Registration Dates

• First Submitted: September 1, 2022
• First Submitted That Met QC Criteria: September 1, 2022
• First Posted (Actual): September 6, 2022

Study Record Updates

• Last Update Posted (Actual): August 15, 2023
• Last Update Submitted That Met QC Criteria: August 14, 2023
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Nervous System Diseases; Neurologic Manifestations; Autonomic Nervous System Diseases; Primary Dysautonomias; Frailty; Hypotension; Hypotension, Orthostatic; Orthostatic Intolerance; Antihypertensive Agents
• Other Study ID Numbers: NL80929.091.22; 2022-001283-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No