Blood Pressure Lowering in Acute Stroke Trial (BLAST)

Hypertension is an important modifiable risk factor for the prevention of ischemic stroke.
Whether specific antihypertensive medications confer an added benefit for recurrent stroke
reduction beyond their ability to lower blood pressure remains a controversial subject.
Because of their varied mechanisms of action, and their potential role as neuroprotective
agents, there has been particular interest in drugs that affect the
renin-angiotensin-aldosterone system (RAAS). Several large multi-national randomized
clinical trials have suggested a unique benefit of these agents, namely angiotensin
converting enzyme (ACE) inhibitors and ARBs, for the prevention of vascular events. Even
with the very modest reductions in blood pressure achieved in the HOPE trial, ramipril was
found to have a significant benefit on recurrent stroke prevention (Heart Outcomes
Prevention Evaluation Study Investigators, 2000). In the LIFE study, losartan was shown to
be more efficacious for the prevention of recurrent strokes in hypertensive patients than
atenolol, despite nearly identical reductions in blood pressure (Dahlöf et al, 2002). This
is an area of some debate, however, as some data may support the lowering of blood pressure
in general over the use of specific agents such as ACE inhibitors for the prevention of
recurrent stroke (PROGRESS Collaborative Group, 2001). More recently, the ACCESS study
showed a benefit of early treatment with candesartan cilexetil on 12-month mortality and the
number of vascular events in patients who had suffered an acute stroke (Schrader et al,
2003). The mechanisms that underlie this are uncertain, but the study suggests that early
treatment of blood pressure in acute stroke may have long-term benefits, presumably
independent of hemodynamic factors.

The use of antihypertensives in the setting of an acute infarct is an area of great
interest. A transient rise in blood pressure is frequently seen in acute stroke patients
(Semplicini et al, 2003). Although blood pressure typically normalizes within one week
without treatment, about one-third of patients remain hypertensive (Britton et al, 1986;
Harper et al, 1994). Currently, there is insufficient data for a clear recommendation on
deliberately altering blood pressure in these acute ischemic stroke patients (BASC, 2004).
That being said, hypertension in acute stroke has been associated with poor outcome (Warlow
et al, 1996), although the relationship may be a 'J'-shaped curve, with both low and high
mean blood pressures being detrimental (Leonardi-Bee et al, 2002). The potential mechanisms
that underlie the association between hypertension and poor outcome in acute stroke are
several, but may include an increase in peri-infarct edema and an increased risk of
hemorrhagic transformation. The potential benefits of the early treatment of high blood
pressure in acute stroke must be weighed against the theoretical risk of worsening ischemia
in compromised neural tissue. The INWEST trial showed increased mortality in patients
actively treated with a calcium-channel blocker within 72 hours of an acute stroke (Wahlgren
et al, 1994), an effect that may be related to the lowering of diastolic blood pressure
(Ahmed et al, 2000). This data is in keeping with the long-standing hypothesis that impaired
autoregulation in the ischemic brain tissue renders cerebral blood flow purely
pressure-dependent. A decrease in systemic blood pressure would then translate to decreased
local perfusion to vulnerable tissue in the ischemic penumbra. It is in this setting that
drugs that modulate the RAAS may have a unique role. In recent years, animal and human data
has accrued that suggests CBF is maintained with these agents, even in the face of decreased
systemic blood pressure.

There are human data regarding cerebral blood flow and drugs that affect the RAAS, in both
normal patients and those with recent ischemia. Studies with ACE inhibitors have
demonstrated a moderate lowering of blood pressure in hypertensive patients, without a
corresponding decrease in CBP, as measure with xenon CT (Minematsu et al, 1987; Waldemar et
al, 1990). Dyker et al (1997) used Doppler ultrasound to show that cerebral blood flow is
maintained in the setting of acute stroke when systemic blood pressure is lowered with
perindopril. A similar result was seen in hypertensive stroke patients with moderate to
severe internal carotid artery stenosis or occlusion (Walters et al, 2001). When losartan
was introduced in hypertensive patients within 2-7 days of a mild ischemic stroke, there was
no adverse effect on global or region cerebral blood flow, as measured by carotid Doppler
and brain hexamethylpropyleneamine oxime single photon emission computed tomography (HMPAO
SPECT; Nazir et al, 2004). There is no published data on the effects of these drugs on
cerebral perfusion as measured with MRI, nor on changes in infarct volume as measure by DWI.

Brain imaging with MRI is available at all major centers that admit patients for the care of
ischemic stroke. Diffusion-weighted imaging is considered the 'gold standard' for the
detection of ischemia in the acute setting, with restricted diffusion being visible within
30 minutes of symptom onset (Fisher and Albers, 1999). Semi-quantitative measures of
cerebral blood flow can be obtained with perfusion-weighted imaging (PWI) with only a
minimal increase in the total scanning time. The acquisition of perfusion data with MRI is
more readily available than such modalities as PET, SPECT, or xenon CT. Data is ongoing to
identify analysis regimens for PWI that best represent true cerebral perfusion. We will use
these techniques to assess brain perfusion before and after the lowering of blood pressure
with valsartan.

We hope to show that valsartan can be used safely in the setting of acute stroke to lower
elevated blood pressure. There are novel properties of this class of drug (an
angiotensive-receptor blocker or ARB), and promising human and animal data, that would
suggest this drug can be safely used to lower blood pressure in the setting of acute stroke
without compromising brain blood flow (i.e. cerebral perfusion). If this is proved to be the
case, this compound could potentially be used routinely in this setting, with the hope of
improving outcome. This pilot study may pave the way for a larger randomized trial looking
at outcome measures in stroke patients. Further, a positive result in the this pilot study
will serve as proof of concept that ARBs maintain cerebral perfusion while decreasing blood
pressure, an overall favorable property.

Inclusion Criteria:

1. Men and non-pregnant women over age 18 who have had an acute ischemic stroke
referable to the anterior circulation, as diagnosed by one of more of the following:
clinical judgment, head CT, and/or MR imaging [i.e. a positive diffusion-weighted
imaging (DWI) abnormality].

2. Clinical syndrome not likely to represent transient ischemic attack (TIA) or other
non-stroke etiology

3. Patient must be neurologically stable at the time of first MRI scan (i.e. stable NIH
Stroke Scale score).

4. Initial MRI scan obtainable within 48 hours of symptom onset.

5. A pre-existing diagnosis of hypertension, either treated or untreated.

6. Average of two mean arterial blood pressures (separated by at least five minutes) at
time of enrollment.

Exclusion Criteria:

1. Patients who have taken an angiotensin-converting enzyme (ACE) inhibitor or
angiotensin receptor blocker (ARB) within seven (7) days of admission.

2. Patients who received intravenous or intra-arterial r-TPA for their current symptoms,
or those who underwent mechanical thrombolysis.

3. Patients with hemorrhagic strokes, as seen on the initial head CT.

4. Patients with stroke-like symptoms, but no demonstrable lesion on DWI, or a DWI
lesion < 2 cm in diameter (greatest dimension).

5. Patients with high-grade (>70%) internal carotid artery stenosis or occlusion
ipsilateral to the current stroke.

6. Patients with high-grade aortic or mitral stenosis.

7. Patients with a previous adverse reaction to valsartan or other ARBs.

8. Patients with contraindications for MRI, including pacemakers, claustrophobia, or
severe obesity.

9. Patients who are medically unstable for MR imaging, as determined by the treating
team.

10. Patients with a severe co-existing disease that may interfere with the conduct of the
study.

11. Patients receiving investigational drug therapies.

12. Informed consent cannot be obtained from the patient or an appropriate surrogate.