Age-specific cerebral haemodynamic effects of early blood pressure lowering after transient ischaemic attack and non-disabling stroke

Introduction There is limited knowledge of the effects of blood pressure (BP) lowering on cerebral haemodynamics after transient ischaemic attack (TIA) and non-disabling stroke, particularly at older ages. We aimed to evaluate changes in transcranial Doppler (TCD) haemodynamic indices in patients undergoing early blood pressure lowering after TIA/non-disabling stroke, irrespective of age. Patients and methods Among consecutive eligible patients attending a rapid-access clinic with suspected TIA/non-disabling stroke and no evidence of extra/intracranial stenosis, hypertensive ones underwent intensive BP-lowering guided by daily home telemetric blood pressure monitoring (HBPM). Clinic-based BP, HBPM, End-tidal CO2 and bilateral middle cerebral artery (MCA) velocity on TCD were compared in the acute setting versus one-month follow-up; changes were stratified by baseline hypertension (clinic-BP≥140/90) and by age (<65, 65–79 and ≥80). Results In 697 patients with repeated TCD measures, mean/SD baseline systolic-BP (145.0/21.3 mmHg) was reduced by an average of 11.3/19.9 mmHg (p < 0.0001) at one-month (133.7/17.4 mmHg), driven by patients hypertensive at baseline (systolic-BP change = −19.0/19.2 mmHg, p < 0.001; vs −0.5/15.4, p = 0.62 in normotensives). Compared with baseline, a significant change was observed at one-month only in mean/SD MCA end diastolic velocity (EDV) (0.77/7.26 cm/s, p = 0.005) and in resistance index (RI) (−0.005/0.051, p = 0.016), driven by hypertensive patients (mean/SD EDV change: 1.145/6.96 cm/s p = 0.001, RI change −0.007/0.06, p = 0.014). Findings were similar at all ages (EDV change – ptrend=0.357; RI change – ptrend=0.225), including 117 patients aged ≥80. EDV and RI changes were largest in 100 patients with clinic systolic-BP decrease ≥30 mmHg (mean/SD EDV change = 2.49/7.47 cm/s, p = 0.001; RI change −0.024/0.063, p < 0.0001). Conclusion There was no evidence of worsening of TCD haemodynamic indices associated with BP-lowering soon after TIA/non-disabling stroke, irrespective of age and degree of BP reduction. In fact, EDV increase and RI decrease observed after treatment of hypertensive patients suggest a decrease in distal vascular resistance.

The Oxford Vascular Study (OXVASC) is a prospective, population-based cohort study of all incident acute vascular events in all territories (transient ischaemic attack, stroke, acute coronary and peripheral vascular events). 1,2 During the period of the current substudy, the OXVASC study population consisted of all 92,728 individuals, irrespective of age, registered with 100 general practitioners (GPs) in nine general practices in Oxfordshire, UK. In the UK, general practices provide primary health care for registered individuals and hold a lifelong record of all medical consultations (from the National Health Service [NHS] and private health care), and details of treatments, blood pressure, and investigations. In Oxfordshire, an estimated 97% of the true residential population is registered with a general practice, with most non-registered individuals being young students. All participating practices held accurate age-sex patient registers, and allowed regular searches of their computerised diagnostic coding systems. The practices had all collaborated on a previous populationbased study, for which they were originally selected to be representative of the urban and rural mix and the deprivation range of Oxfordshire as a whole. 3 Based on the index of multiple deprivation (IMD), the population was less deprived than the rest of England, but had a broad range of deprivation.
The OXVASC population is 94% white people, 3% Asian, 2% Chinese, and 1% Afro-Caribbean. 4 The proportion of whites is similar to that of the UK as a whole (88% white) and to many other western countries (Australia -90%; France -91%; Germany -93.9%).

Case ascertainment
After a 3-month pilot study, the study started on April 1, 2002, and is ongoing. Ascertainment combined prospective daily searches for acute events (hot pursuit) and retrospective searches of hospital-care and primary-care administrative and diagnostic coding data (cold pursuit).
Hot pursuit was based on: or who died soon after. 5. Daily searches of lists of all patients from the study population in whom a troponin-I level had been requested. 6. Daily assessment of all patients undergoing diagnostic coronary, carotid and peripheral angiography, angioplasty, stenting or vascular surgical procedures in any territory to identify both total burden of vascular invention and any potential missed prior acute events.
Cold pursuit procedures were: 1. Frequent visits to the study practices and monthly searches of practice diagnostic codes. 2. Monthly practice-specific list of all patients admitted to all acute and community NHS hospitals. 3. Monthly listings of all referrals for brain or carotid imaging studies performed in local hospitals. 4. Monthly reviews of all death certificates and coroners reports to review out-ofhospital deaths. 5. Practice-specific listings of all ICD-10 death codes from the local Department of Public Health.
Patients found on GP practice searches who have an event whilst temporarily out of Oxfordshire are included, but visitors who were not registered with one of the study practices are excluded. A study clinician assessed patients as soon as possible after the event in the hospital or at home. Informed consent was sought, if possible, or assent was obtained from a relative. Data are collected using event-specific forms, for TIA and stroke, acute coronary syndrome or acute peripheral vascular events. Standardised clinical history and cardiovascular examination are recorded. Information recorded from the patient, their hospital records and their general practice records includes details of the clinical event, medication, past medical history, all investigations relevant to their admission (including blood results, electrocardiography, brain imaging and vascular imaging-duplex ultrasonography, CT-angiography, MR-angiography or DSA) and all interventions occurring subsequent to the event.
If a patient died before assessment, we obtained an eyewitness account of the clinical event and reviewed any relevant records. If death occurred outside the hospital or before investigation, the autopsy result was reviewed. Clinical details are sought from primary care physicians or other clinicians on all deaths of possible vascular aetiology.
All surviving TIA and stroke patients are followed-up face-to-face at 1, 6, 12, 60 and 120 months after the initial event by a research nurse or physician and all recurrent vascular events were recorded together with the relevant clinical details and investigations. If face-toface follow up is not possible, telephone follow-up is performed or enabled via the general practitioner. All recurrent vascular events that presented to medical attention would also be identified acutely by ongoing daily case ascertainment within OXVASC. If a recurrent vascular event was suspected at a follow-up visit or referred by the GPs to clinic or admitted, the patient was re-assessed and investigated by a study physician.

Definitions of events
Although new definitions for stroke and TIA have been suggested recently, 4,5 in order to enable comparison with previous studies, the classic definitions of TIA and stroke are used throughout. 6 A stroke is defined as rapidly developing clinical symptoms and/or signs of focal, and at time global (applied to patients in deep coma and to those with subarachnoid haemorrhage), loss of brain function, with symptoms lasting more than 24 hours or leading to death, with no apparent cause other than that of vascular origin. 6 A TIA is an acute loss of focal brain or monocular function with symptoms lasting less than 24 hours and which is thought to be caused by inadequate cerebral or ocular blood supply as a result of arterial thrombosis, low flow or embolism associated with arterial, cardiac or haematological disease. 4 All diagnoses were reviewed by a senior neurologist (PMR). With the high rate (97%) of imaging or autopsy in OXVASC, strokes of unknown type were coded as ischaemic.

Brain and vascular imaging
During the acute clinical assessment, brain and vascular imaging are obtained, either 3T magnetic resonance imaging (MRI) with time-of-flight magnetic resonance angiography (MRA) of the intracranial vessels and a contrast-enhanced MRA of the large neck arteries, or brain computed tomography (CT) with contrast-enhanced CT angiography or Duplex ultrasound if MRI is contraindicated. 7

Transcranial Doppler and capnometry protocol
Middle cerebral artery blood flow velocity was recorded with a handheld 2 MHz probe through temporal bone window at the depth that provided the best signal, usually 50 mm. Transcranial Doppler (TCD) examination was conducted in a quiet room, with the patient lying comfortably on a couch, having a lying blood pressure measure taken before and after the scan. Each session was stored in the hard disk of the TCD device for subsequent off-line analysis. 8 End-tidal CO2 was monitored via nasal cannulae (Capnocheck Plus; Smith Medical) throughout the procedure at each time point.

Home blood pressure monitoring
Patients were fitted with a Bluetooth-enabled telemetric blood pressure monitor (IEM Stabilo-Graph or A&D UA-767 BT) in clinic on the day of assessment (or at the earliest opportunity). After appropriate training, they were instructed to perform sets of three home readings in the non-dominant arm, or the arm with the higher reading (if mean blood pressure differed by >20mmHg between arms), three times daily (on waking, mid-morning and before sleep). Measurements were transmitted by Bluetooth radio to a mobile phone or Raspberry Pi microcomputer hub for secure transmission to a server, hosting a passwordprotected website for review and download of readings (t+ Medical, Abingdon, UK), and were assessed daily by the OxVasc team. Patients continued home monitoring until at least the one month follow-up appointment, if tolerated. 9 Home blood pressure monitoring (HBPM) readings for each participant were downloaded from the encrypted website and manually assessed to remove those with erroneous measures or incorrect date/time stamps (n=23, <0.1%). Recordings with SBP <50 mmHg (n=1), DBP >140 mmHg if pulse pressure <40 mmHg (n=2), and any pulse pressure <10 mmHg (n=2) were excluded. The first three days of HBPM were used for diagnosis of hypertension (BP ≥135/85mmHg). If the first HBPM reading coincided with the date and time of the baseline clinic reading, this was excluded, as some patients were instructed to take a test reading as part of their instruction in clinic on how to use the HBPM kit.