Hypertensive treatment in elderly with cerebral small vessel disease: should we SPRINT faster?

There is an ongoing dilemma for clinicians deciding which hypertensive
treatment target should be used in hypertensive older patients. In recently
developed recommendations for hypertension by the Eight Joint National
Committee (JNC 8) got revised for patients 60 years and older, i.e. 150mmHg
instead 140mmHg systolic BP (SBP) cut-off. These panel members published a
minority report stating that the currently available evidence does not support
new less stringent systolic cut-off values for older persons. Strikingly, the
recently published SPRINT trial * a randomized trial of intensive versus
standard BP control * confirmed their statement (Wright et al. NEJM 2015). The
SPRINT trial showed that among adults, including those older than 70 years,
lowering SBP to a target less than 120mmHg, as compared with the standard goal
of less than 140mmHg, resulted in significantly lower rates of fatal and
non-fatal cardiovascular events and death from any cause in the long term.
So far, all available trials, including the SPRINT trial, mainly included
healthy older participants with little or no co-morbidity, a healthy vascular
system, and normal physical and cognitive functioning. It is not clear is these
results can be translated to routinely daily practice in which doctors
encounter less healthy older subjects.
Under healthy physiologic conditions, blood flow to the brain is tightly
regulated by a harmonized function of the systemic and cerebral circulation.
This tight regulation aims to optimize the combination of blood flow and
perfusion pressure at the tissue level to maintain adequate brain perfusion,
despite fluctuations in systemic BP. With age cerebral blood flow (CBF)
declines due to damage in the circulation and in particular the small vessels.
Hence, higher perfusion pressures are necessary to maintain adequate brain
perfusion. In patients with microvascular brain lesions, brain autoregulation
becomes less efficient making the brain more dependent on systemic BP levels
(Novak et al. Neurology 2003).
Although little evidence is available, an experimental study in diabetic
patients showed a decline in CBF with more intensive BP control (Kim et al
Hypertension 2011). The short-term effect of intensive BP control on CBF in
patients with hypertension and cerebral small vessel disease has never been
studied. Furthermore, the (long-term) effect of possible decreasing CBF is on
cognition and cerobral vascular lesions, has never been studied before.

The main objective of this effectiveness study is to test if intensive control
(SBP *120 mmHg) decreases cerebral blood flow velocity compared to conventional
targets (SBP<140-150 mmHg) in patients with CSVD and hypertension. Secondary
objectives are to test the effect of tight blood pressure control on cognitive
functioning, degree of white matter lesions, orthostatic hypotension, dynamic
cerebral autoregulatory capacity, CO2 responsiveness, premature trial
termination because of unacceptable drug side effects.

Randomized controlled intervention study.

The intervention group will be treated using SPRINT-targets (SBP *120mmHg) and
the control group using conventional blood pressure targets (SBP<140-150mmHg).

Patients will visit the Academic Medical Centre (AMC) Amsterdam twice (at
baseline and at the end of the trial after 4 months) for several non-invasive
measurements; Blood pressure will be measured continuously using
finger-plethysmography (a small cuff wrapped around the middle finger).
Continuous CBF velocity will be measured bilaterally with TCD at the middle
cerebral artery in lying and standing position and
during repeated sit-stand manoeuvers. For this, patients will be wearing a head
band with external probes. Peripheral oxygenation will be measured using
stickers on the patient's chest. Participants could experience some physical
discomfort from the head band and/or chest stickers. During their first and
second visits at the AMC, patients will be asked to perform the DSST, a
neuropsychiological test on a computer which takes appr. 1-3 min. During their
second visit the following cognitive tests will also be performed: Mini Mental
State Examination (MMSE, questionnaire), the Stroop Color and Word Test (on a
computer) and the 15 Words Memory Test (questionnair). A questionnaire
assessing orthostatic complaints and falling will also be filled in. These
tests take appr. 20 min in total to complete. The MMSE, 15 words memory test,
Stroop test and the questionnaire assessing orthostatic complaints are
performed at baseline during the standard work-up at the outpatient clinic.

During their 'treat-to-target-phase' patients will be asked to measure their
blood pressure every two weeks during 3 consecutive days. Possible experiences
symptoms and their blood pressure values will be written down in a personal
diary. Two weeks after starting their antihypertensive treatment patients will
be seen at the VUmc outpatient clinic to evaluate the therapy and their lab
results. This is part of their 'regular care' and not an extra hospital visit/
blood sampling. During the following weeks patients will recieve a Phone call
every 2 weeks to evaluate their treatment and necessarily adjust their drug
regime. In case of drugs side-effects/complaints participants can contact
assistant researcher dr. Emma Kleipool. She will contact the geriatrician on
call. If she is not available, patients can contact the geriatrician who is on
call directly. Every VUmc geriatrician is familiar with this trial. The
geriatrician decides what further steps need to be taken (e.g. visit COGA
outward patient clinic, visit to the emergency department, potential
adjustments to/ discontinuation of antihypertensive medication). Adjustments to
a patient*s treatment will not be based on the exact height of the diastolic
blood pressure. Observational studies suggest that diastolic BP levels below 70
mmHg are associated with an increased mortality risk in the oldest old (80
years and older) (Mattila et al. 1988, Satish et al. 2001). However, it is
unclear if low diastolic BP is a risk factor for mortality or if it is an
indicator of co-morbidity of frailty and therefore associated with a lower
survival. However, in intervention studies, this observation has not been
replicated.

No extra blood samples will be taken and no extra physical examination will be
performed.

The risk to and burden for the subject will be moderate. Patients could
experience symptoms related to decreasing blood pressure (head ache, dizziness,
orthostatic complaints) with an accompanying increased of falling. Furthermore,
acute decreasing kidney function, eletrolyte disorders and drug specific side
effects such as a dry cough (ACE-inhibitor), bradycardia (betablocker calcium
channel blicker), ankle oedema (calcium channel blocker). However, blood
pressure treatment will be done in a controlled matter supervised by a
geriatrician based on systolic blood pressure ánd drug side effects. In case of
experiencing unacceptable side effects, blood pressure will not be loweredany
further. Antihypertensive drugs will be discontinued or the dose will be
lowered in order to achieve blood pressure targets at which the patients does
not experience these symptoms. Considering these actions, negative effects of
blood pressure will be avoided as much as possible.