Study design
Patients included
No. of patients with ischemic stroke
Intervention vs. control
Mean time from stroke onset to randomization, h
Outcome assessments
Results
Con studies against BP lowering
BEST, 1988
Randomized trial
Any stroke within 48 h after stroke
NA 302 (any stroke)
Propranolol, or atenolol vs. placebo 21 days or until discharge
NA
Neurologic recovery, discharge state, functional outcome, death at 30 days and 6 months
Higher death rate in the treatment arm at 6 months and no difference of neurologic recovery and functional outcome at 6 months
INWEST, 2000
Randomized, double-blinded, placebo-controlled trial
Ischemic stroke within 24 h in the carotid artery territory
295
Intravenous nimodipine vs. placebo 21 days
11
Death or dependency (BI < 60) at day 21 days
Higher rate of death and worse neurologic recovery by reduction of diastolic BP (>20%) after high-dose nimodipine
SCAST, 2011
Randomized, double-blinded, placebo-controlled trial
Any stroke within 30 h after stroke, SBP ≥140 mm Hg
1733
Candesartan vs. placebo for 7 days
NA
mRS > 2 at 6 months, vascular events at 6 months
No beneficial effect but a trend toward increased risk of vascular events and worsening functional outcome at 6 months in the treatment arm
VENTURE, 2015
Randomized, open, blinded end point, controlled trial
Ischemic stroke within 48 h after stroke, SBP 150 to 185 mm Hg
372
Valsartan vs. no antihypertensive agents for 7 days
NA
Death or functional dependency (mRS > 2) at 90 days; END at 7 days, vascular events and BI at 90 days
No beneficial effect in death or dependency at 90 days but trend to increased risk of END in the treatment arm
Pro studies supporting BP lowering
ACCESS, 2003
Randomized, double-blinded, placebo-controlled trial
Ischemic stroke within 36 h, SBP ≥ 200 mm Hg and DBP ≥ 110 mm Hg
339
Candesartan vs. placebo for 7 days
30
Vascular events and death at 12 months; BI at 3 months
No difference in functional dependency at 3 months but reduction of vascular events and death at 1 y in the treatment arm
CHHIPS, 2009
Randomized, double-blinded, placebo-controlled trial
Any stroke within 36 h after stroke, SBP > 160 mm Hg
99
Labetalol, or lisinopril vs. placebo for 14 days
NA
mRS > at 14 days
No difference in death or neurologic recovery at 2 weeks but reduction in death at 3 months with treatment group
Studies with neutral results
COSSACS, 2010
Randomized, open, blinded end point trial
Any stroke within 48 h after stroke, pre-existing, hypertension agents
444
Continuous or stop pre-existing antihypertensive agents for 14 days
NA
Death or functional dependency (mRS > 3) at 14 days
No difference in death or dependency at 2 weeks
No difference in death or recurrent stroke at 6 months
PRoFESS substudy, 2009
Randomized, double-blinded, placebo-controlled trial
Ischemic stroke within 72 h after stroke, SBP 121 to 180 mm Hg
1360
Telmisartan vs. placebo for 90 days
58
mRS at 30 days, death at 90 days; stroke recurrence, combined vascular at 90 days
No difference in dependency, death, or recurrent stroke at 3 months
CATIS, 2014
Randomized, open, blinded end point, controlled trial
Ischemic stroke within 48 h after stroke, SBP 140 to 220 mm Hg
4071
Antihypertensive agents vs. discontinue all antihypertensive agents during hospitalization
15
mRS at 14 days (or discharge) and 90 days; vascular events, recurrent stroke, and death at 90 days
No difference in death and dependency at 14 days or at discharge
No difference in death or dependency at 3 months
ENOS, 2015
Randomized, open, blinded end point, controlled trial
Any stroke within 48 h after stroke, SBP 140 to 220 mm Hg
3342
Transdermal GTN vs. no transdermal GTN for 7 days/continuing vs. stop antihypertensive agents
NA
mRS > 2 at 90 days after enrolment
Neutral effect on functional outcome at 90 days, but some benefit in a subgroup of administration within 6 h
24.2.1 Con Studies Against Early BP Lowering
The Low-Dose Beta Blockade in Acute Stroke (BEST, 1988) [5]: The BEST trial revealed a higher rate of mortality among patients who were treated by beta-blocker therapy within 48 h of symptom onset.
The Intravenous Nimodipine West European Stroke Trial (INWEST, 2000) [6]: The INWEST trial found a significant correlation between prominent DBP lowering with intravenous nimodipine and worsening of clinical outcomes at 21 days after stroke onset. Higher rates of death and disability were statistically significant associated with a decrease in DBP > 20% or DBP < 60 mm Hg. A subsequent meta-analysis of the studies of oral nimodipine started within 48 h after stroke onset also showed that the BP lowering with oral nimodipine did not improve functional outcome at 3 months but was significantly associated with higher rates of mortality.
The Scandinavian Candesartan Acute Stroke Trial (SCAST, 2011) [3]: In the SCAST trial, BP was significantly lower in the treatment group, 147/82 mm Hg for the candesartan group vs. 152/84 mm Hg for the placebo group. However, there was no significant difference in the composite outcome of vascular death, myocardial infarction, or stroke during the first 6 months, but a nonsignificant trend toward worse functional outcome at 6 months. The study concluded BP lowering with candesartan showed no benefit in patients with acute stroke. If anything, the evidence suggested a harmful effect. In addition, subgroup analysis of the SCAST demonstrated that large SBP change was associated with the increased risk of early adverse event and early neurological deterioration.
The Valsartan Efficacy on Modest Blood Pressure Reduction in Acute Ischemic Stroke (VENTURE, 2015) [7]: Valsartan started within 48 h after stroke onset did not reduce rates of death or dependency and vascular events at 3 months, but significantly increased the risk of early neurological deterioration at 7 days.
24.2.2 Pro Studies Supporting Early BP Lowering
The Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS, 2003) [8]: The ACCESS trial showed that, in the absence of BP lowering, candesartan for 7 days initiated within 24 h of stroke onset significantly reduced the morality and vascular events at 12 months. The trial concluded that candesartan is safe to use in the acute setting of ischemic stroke and may have therapeutic benefits, irrespective of lowering BP effect.
The Controlling Hypertension and Hypotension Immediately Post-Stroke (CHHIPS, 2009) [9]: In the CHHIPS trial, there was no difference in 14-day mortality and disability. However, the rate of 90-day mortality was reduced in receiving antihypertensive therapy, but clinical significance was borderline. In addition, there was no increase in adverse event (early neurological deterioration) in the treatment group receiving oral and sublingual lisinopril and oral and intravenous labetalol.
24.2.3 Studies with Neutral Results
The Continue or Stop Post-Stroke Antihypertensives Collaborative Study (COSSACS, 2010) [10]: The COSSACS trial was aimed at establishing the safety and efficacy of stopping vs. continuing prior prescribed antihypertensive agents in acute ischemic stroke. Continuation of antihypertensive agents did not reduce death or dependency at 2 weeks, cardiovascular event rate, or mortality at 6 months. Furthermore, lower BP in those who continued antihypertensive agents were not associated with an increased risk in adverse events. These neutral results might be because the study was underpowered owing to early termination of the trial.
In a substudy of the Prevention Regimen for Effectively Avoiding Second Strokes trial (PRoFESS substudy, 2009) [11]: In a substudy of the PRoFESS trial, treatment with telmisartan in 1360 patients enrolled within 72 h appeared to be safe without increasing adverse events, but was not associated with a significant effect on functional dependency, death, or stroke recurrence. The results of a substudy of the PROFESS trial suggest that it is safe to initiate antihypertensive therapy in the first 72 h after acute ischemic stroke.
The second trial is the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS, 2014) [12]: The CATIS trial concluded that the early BP lowering with antihypertensive agents had no effect on the incidence of death and major disability at 14 days or at hospital discharge when compared with the absence of treatment. There was also no difference in the rate of death or major disability at 3 months between the two groups.
The Efficacy of Nitric Oxide in Stroke trial (ENOS, 2015) [13]: The ENOS trial demonstrated that there was a neutral effect on modified Rankin Score at 90 days with either glyceryl trinitrate (GTN) compared with no GTN or continuing prestroke antihypertensive drugs compared with stopping them temporarily. However, some benefit was reported in the subgroups given GTN within 6 h of stroke onset.
Data from recent meta-analysis of 13 randomized controlled BP lowering trials in acute ischemic stroke showed a neutral effect of early BP lowering in the setting of acute ischemic stroke on the prevention of death, functional dependency, and recurrent vascular events including stroke [14].
24.2.4 Management of BP
Optimizing hypertensive managements in acute ischemic stroke are discussed based on the currently available evidence including results of these summarized clinical trials. The key clinical questions of early BP lowering in the setting of acute ischemic stroke include following.
When to start BP lowering? The meta-analysis of oral nimodipine trials showed a benefit from nimodipine when given within 12 h after stroke onset, no benefit between 12 and 24 h, and worse outcome when initiated after 24 h. In the SCAST, the benefit of candesartan was seen in a small subgroup started within 6 h, but when the later treatment was initiated, the more did candesartan seem to result in harm regarding the composite vascular events. Recent results of a subgroup analysis of ENOS study also found that the transdermal GTN was safe to administer and significantly associated with improved functional outcome and few deaths when treated within 6 h of stroke onset [15]. However, CHHIPS, COSSACS, CATIS, and VENTURE trials that started treatment later were all neutral or negative effect, even with a small benefit in secondary outcomes. These results, taken together, suggest that there is a small benefit in the earlier BP treatment and trend toward less benefit with increasing time to treatment. The effectiveness of the earlier BP lowering may be proven by forthcoming trials on the earlier management of hypertension in the acute phase of stroke including the earlier Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial (RIGHT) and Field Administration of Stroke Therapy-Magnesium (FAST-MAG) trial.
How fast and how much to lower BP? In the INWEST trial, the high-dose intravenous nimodipine was associated with death and dependency when DBP was lowered by more than 20% within the first 48 h after stroke onset. In post hoc analysis of the SCAST trial, large SBP decrease of more than 28 mm Hg was also significantly associated with poor functional outcome at 6 months. However, the CHHIPS trial showed that the gradually moderate BP lowering seems safe and even protective. A difference of SBP with 10 mm Hg over 24 h reduced 90-day mortality, and this did not increase early neurological deterioration at 72 h. So the rapid and large reduction of BP seems to be dangerous for patients with acute ischemic stroke. These results support a cautious BP lowering with gradual titration and modest reduction to more aggressive BP treatment targets. Current consensus guidelines recommend that a cautious BP reduction by below 15% of initial BP for the first 24 h of stroke onset should be as gradual and as modest reduction.
Is it safe to lower BP in patients with large artery stenosis? BP reduction is associated with an increased risk of early neurological deterioration and worse outcomes in some studies. The data from VENTURE trial showed the association between the early BP reduction with valsartan and the early neurological deterioration within 7 days, particularly in patients with subtype of large artery atherosclerotic stroke or significant large artery stenosis, although a causal relationship had not been demonstrated conclusively. Conversely, several data showed that BP reduction is safe in terms of early neurological deterioration and functional outcome, even in the presence of carotid artery stenosis [13]. To date, there is no specific prospective randomized trial to evaluate the impact of protocol of BP lowering in the specific subtypes of ischemic stroke. However, it is cautious to aggressive BP lowering in patients with significant large artery disease combined to poor collateral flow on vascular imaging.
Which drugs to select? Another aspect further considered is which class of antihypertensive medication is appropriate for management of acute hypertensive response, but there is no clear answer to this question as yet. Direct acting cerebral vasodilators adversely affect CBF and may be potential to increase ICP. The calcium channel blocker nimodipine had a positive effect when given orally within 12 h, but a negative effect when given intravenously in the INWEST trial. The angiotensin-converting enzyme inhibitor (ACEI) had a positive effect in the CHHIPS trial, but a neutral effect in the CATIS trial. Other trials of the angiotensin-receptor antagonist during the acute phase of stroke have shown that the drug possibly was associated with a worse outcome in the SCAST and VENTURE trials. The mixed alpha-/beta-receptor blocker (labetalol) showed a low rate of 3-month mortality in the CHHIPS trial; conversely the oral beta-blocker agents (propranolol, atenolol) were associated with a higher rate of mortality in the BEST. A recent Cochrane review addressed BP lowering in acute stroke concluded that none of BP lowering agents affected in either mortality or functional outcome [15]. In general, antihypertensive agents that have rapid onset of action and are short acting and easy to titrate are most relevant in the setting of acute ischemic stroke. The AHA/ASA guidelines recommend antihypertensive agents for acute hypertensive response that are either intravenous or transdermal agents with easy titration to consider ability to swallow (Table 24.2).
Table 24.2
Pharmacological agents for early BP lowering in ischemic stroke
Class | CBF change | Dose | Onset of action | Duration of action | |
|---|---|---|---|---|---|
Labetalol | Adrenergic antagonist beta-blocker | … | 5–20 mg bolus every 15 min, up to 300 mg | 5–10 min | 3–6 h |
Nicardipine | Calcium channel blocker | + | 5–15 mg/h, increase by 2.5 mg/h every 5–10 min | 5–10 min | 0.5–4 h |
Nitroglycerine | Nitrate | + | 10–400 mg/min | 1–2 min | 3–5 min |
Sodium nitroprusside | Nitrate | ++ | 0.2–10 mg/kg/min | <1 min | 2–5 min |
Esmolol | Beta adrenergic blocker | … | 250 μg/kg bolus followed by 25 to 300 g/kg/min | 5 min | 9 min |
Enalapril | ACE inhibitor | … | 1.25–5 mg every 6 h | 15 min | 1–4 h
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