The results of the China Antihypertensive Trial in Acute
Ischemic Stroke (CATIS) study were presented last month at
the 2013 American Heart Association Scientific Meeting and
simultaneously published in the Journal of the American
Medical Association [1]. The CATIS study was a multicenter,
controlled, randomized study that aimed to assess the
effects of blood pressure reduction during the acute phase of
ischemic stroke on death and major disability at 14 days and
3 months after the episode. The stroke was confirmed by
brain CT or MRI and systolic blood pressure levels between
140-220 mmHg were required to enter the study. About half
of screened patients with an acute ischemic stroke and hypertension
fulfilled all inclusion/exclusion criteria and entered
the study (2,038 out of 4,071).
Study participants were randomly assigned to receive or
not antihypertensive therapy within 48 hours of stroke onset.
In particular, a graded blood pressure reduction was aimed in
the active group targeting a 10-25% reduction during the
first study day and blood pressure control during the first
week post-randomization. In contrast, no antihypertensive
therapy was given in the control group and previous antihypertensive
medication was discontinued during the acute
phase of stroke. After the first week, all patients received
antihypertensive therapy to achieve blood pressure control
(<140/90 mmHg).
Blood pressure was significantly reduced in both groups
during the first 24h post-randomization; however, the reduction
was significantly greater in the active compared to the
control group (21.8 versus 12.7 mmHg; between group difference:
9.1 mmHg; 95% CI: 8.1-10.2; p<0.001). Similarly,
blood pressure levels were significantly lower in the active
group at 7 days post-randomization (between group difference
9.3 mmHg; 95% CI: 8.4-10.1; p<0.001). The primary
outcome (death or major disability at 14 days or hospital
discharge) was identical in the two groups (odds ratio: 1.00;
95% CI: 0.88-1.14; p=0.98). The secondary outcome (death or major disability at 3 months post-randomization) was also
the same (odds ratio: 0.99; 95% CI: 0.86-1.15; p=0.93), despite
lower blood pressure values in the active group.
Subgroup analysis did not reveal any significant differences
between the two groups on study outcomes. Blood
pressure reduction during the acute phase of stroke seemed
to confer a significant benefit only in one subgroup of patients:
those who received antihypertensive therapy after the
first 24h of stroke onset (odds ratio: 0.73; 95% CI: 0.55-
0.97; p=0.03). It has to be noted however that the findings of
the subgroup analysis should always interpreted with caution,
and be considered rather as hypothesis generating than
conclusive.
The results of the CATIS study add more gas on the debate
about the management of elevated blood pressure during
the acute phase of an ischemic stroke. Current guidelines
recommend blood pressure lowering in acute ischemic stroke
only when blood pressure levels are above 220/120 mmHg
[2]. However, such patients represent a minority, with less of
1% of patients admitted for stroke [3]. Therefore, a therapeutic
strategy for the vast majority of stroke patients with elevated
blood pressure is of utmost importance for practicing
clinicians.
Available data in this field is unfortunately limited and
inconclusive. About a decade ago, the Acute Candesartan
Cilexitil Therapy in Stroke Survivors (ACCESS) study created
a lot of enthusiasm [4]. A significantly lower rate of
vascular events and all-cause mortality at 12 months was
observed with candesartan compared to placebo (odds ratio:
0.475; 95% CI: 0.252-0.895), and the study was prematurely
terminated when almost 350 patients were randomized instead
of the projected 500 patients.
The ACCESS study questioned the negative findings of
the Intravenous Nimodipine West European Stroke Trial
(INWEST) [5], and set the basis for the conduction of a
larger study, the Scandinavian Candesartan Acute Stroke
Trial (SCAST). In the latter study, candesartan was compared
to placebo in more than 2,000 patients with acute
stroke, either ischemic or hemorrhagic [6]. Unfortunately,
the great expectations generated by the ACCESS study were not fulfilled. There was no significant difference in the outcome
between the active and the placebo group of the trial.
In the meantime, two other smaller studies were published.
The Controlling Hypertension and Hypotension Immediately
Post-Stroke (CHHIPS), a placebo-controlled, randomized
study of 179 patients with acute stroke compared
the effects of labetalol, lisinopril, and placebo [7]. No significant
differences between the active and the comparison
groups were observed, apart from a marginal benefit in mortality
at 3 months post-stroke (hazard ratio: 0.40; 95% CI:
0.2-1.0; p=0.05). The Continue or Stop Post-Stroke Antihypertensives
Collaborative Study (COSSACS) compared
the effects of continuation or withdrawal of prior antihypertensive
therapy in 763 patients with an acute mild stroke [8].
Continuation of antihypertensive therapy did not confer any
benefit in mortality or disability.
Taken together, the findings of the CATIS trial combined
with the findings of previous trials point towards a neutral
effect of antihypertensive therapy during the acute phase of
an ischemic stroke. Whether the time of therapy initiation
(>24h from stroke onset) or other yet unidentified factors
play a role and might identify patient subgroups who will
benefit from antihypertensive therapy remains to be clarified
by future research. Until then, the ‘non-detrimental – nonbeneficial’
effect of antihypertensive therapy suggests the
individualization of management during the acute stroke by
treating physicians.
Response by Mulder et al to Letter Regarding Article, “Baseline Blood Pressure Effect on the Benefit and Safety of Intra-Arterial Treatment in MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands)”
