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.
