Michelle Christina Johansen, MD

Jusufovic M, Sandset EC, Bath PMW, and Berge E, on behalf of the Scandinavian Candesartan Acute Stroke Trial Study Group. Blood Pressure–Lowering Treatment With Candesartan in Patients With Acute Hemorrhagic Stroke. Stroke. 2014

Never has the mantra an ounce of prevention is worth a pound of cure rung truer than in the field of Vascular Neurology. Hypertension remains the most important risk factor for both ischemic and hemorrhagic stroke. It has been well proven that blood pressure lowering to a goal of normotensive strongly correlates with decreased stroke risk in primary prevention, but the question then becomes how and when to treat blood pressure in acute stroke? 

Expert data generally recommends permissive hypertension (220/120mm Hg) if not treated with thrombolytics for the first 24 hours. Acute hemorrhagic stroke presents a particularly difficult situation. Blood pressures tend to run high in these patients and this has been found to be an independent predictor of poor prognosis. The Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) enrolled 404 patients after acute intracerebral hemorrhage to either an intensive blood pressure lowering arm (≤140mmHg in one hour maintained for seven days) or guideline based therapy (goal systolic of 180mmHg). The first phase of this study published in 2008 found intensive lowering of blood pressure was feasible and associated with a decreased relative risk of hematoma growth.  The primary outcome in the final analysis (INTERACT2) was death or major disability using the modified Rankin score (mRS). There was a significantly lower mRS in patients undergoing intensive therapy with no increase in mortality or nonfatal serious events.

Jusufovic et al sought to re-evaluate this important question by using data from the Scandinavian Candesartan Acute Stroke Trial (SCAST). The group isolated the 274 patients with hemorrhagic stroke from the original cohort in an effort to re-evaluate the trial’s original primary end points: composite of vascular death, stroke or myocardial infarction as well as mRS at 6 months. In the original SCAST trial, patients were randomized to Candesartan or Placebo around 18hrs after stroke onset. Therapy was continued for 7 days with dose escalation from 4mg to 16mg over a period of days. The new analysis performed by Jusufovic et al demonstrated that isolation of those with hemorrhagic stroke from the original population did not change the final interpretation. There was no benefit of Candesartan in any of the cohorts and was statistically associated with a poorerfunctional outcome.

Does this then present a paradox? How is the vascular neurologist to proceed?  The authors importantly point out fundamental differences between the two trials that are important to consider in analysis of the data. The SCAST trial did not implement therapy until 18hrs after stroke onset while the intensive arm of INTERACT lowered blood pressure within one hour. It is also notable that 90% of patients in the intensive arm of INTERACT used some type of intravenous therapy during the study with great variance in the agent chosen.  Notably 32% was an alpha-adrenergic antagonist. SCAST utilized an angiotensin receptor blocker. As has been raised in criticism of INTERACT, the different mechanisms of the various antihypertensives clearly play an important role. So where does this leave the clinician? Hypertension is a risk factor yet hypotension has been associated with recurrent stroke and the SCAST study suggests that Candesartan is associated with a worse outcome!      
A better understanding of which clinical characteristics are associated with benefits from antihypertensive therapy paired with the understanding that timing of therapy remains essential in all aspects of stroke care must continue to guide our research in the future.