ENOS: No Rush to Continue Oral BP Meds in Acute Stroke

May 09, 2014

NICE, France — A new trial shows a neutral result for the primary outcome on the question of whether to continue or stop preexisting antihypertensive medication in the acute phase of stroke.

But some secondary outcomes were better in patients who stopped taking their antihypertensive medication for the week of the stroke.

"There is no evidence to support the policy of continuing prestroke blood pressure–lowering therapy in patients in the acute phase of stroke," lead investigator, Professor Philip Bath, University of Nottingham, United Kingdom, concluded.

Much of the harm in the group continuing medication was attributed to pneumonia in patients who had dysphagia (difficulty swallowing), suggesting the hazard of aspiration of medication in patients unable to swallow properly.

Results of the Efficacy of Nitric Oxide and Stroke (ENOS) trial were presented here at the XXIII European Stroke Conference (ESC).

The trial also tested the administration of transdermal glyceryl trinitrate (GTN), a nitric oxide donor, in the acute phase of stroke and also showed a neutral result for this intervention, although there did appear to be some benefit in patients treated very early.

"We asked 2 questions, both about the acute phase of stroke: Should we lower blood pressure with transdermal GTN, and should we stop or continue existing blood pressure medication?" Professor Bath commented to Medscape Medical News.

Dr. Philip Bath

The GTN answer was neutral in terms of the primary endpoint, functionality on the modified Rankin scale (mRS). But there appeared to be some benefit in patients treated very early, within 6 hours of symptom onset.

"This is interesting as a previous small study (RIGHT [Rapid Intervention with Glyceryl trinitrate (GTN) in Hypertensive stroke Trial]) also suggested a benefit of early treatment with GTN," he said. "It is very unusual for a subgroup of a larger trial to show the same thing as a previous smaller study, but this is what has happened here."

He is now seeking funding to conduct another large study (RIGHT-2) of just early treatment.

Caution With Oral Meds in Dysphagia

On the question of whether patients who are already taking antihypertensive medication should have that medication continued or stopped during the acute phase of stroke, the trial also reached a neutral answer for the primary outcome.

But there was an increase in the number of cases of pneumonia in patients who continued their medication, which appeared to be restricted to patients with dysphagia.

Professor Bath concluded: "I would suggest from these results that antihypertensive treatment can be continued once a patient is stable and safe enteral access has been established. But there is no urgency to immediately restart treatment in the first week."

He added: "If the patient had had a mild stroke and had recovered well I would be happy to restart their antihypertensive medication. But if they had had a severe stroke, the important message from ENOS is that they should be stabilized first and swallowing established before restarting any oral medication.

"Junior doctors in the emergency department seem to feel obliged to get the blood pressure medication back on board as soon as possible, but these results are saying don't rush it."

ENOS was a randomized, partial-factorial trial in which 4000 patients with acute stroke (both ischemic and hemorrhagic) were randomly assigned to 5 mg transdermal GTN or placebo for 1 week (patient blinded), and those who were already taking blood pressure–lowering medication were further randomly assigned (open label) to continuing or stopping their medication.

 
Junior doctors in the emergency department seem to feel obliged to get the blood pressure medication back on board as soon as possible, but these results are saying don't rush it. Dr. Philip Bath
 

Early Role for GTN?

Professor Bath explained the rationale for testing GTN in acute stroke. It is a nitric oxide donor that also lowers blood pressure and has shown neuroprotective effects in animal models. It can be given transdermally, so it is easy to administer in acute stroke when patients may not be able to take oral medication. It is also relatively inexpensive.

For the GTN part of the trial, the initial blood pressure difference between the 2 groups was 7.0/3.7 mmHg. Professor Bath said this was smaller than expected but because hypotension was present in the GTN group, the blood pressure difference probably reflected suboptimal measurement times.

Results showed that the primary outcome — shift in mRS score at 90 days — was completely neutral (odds ratio, 1.01). Secondary outcomes at 7 days were also neutral apart from headaches and hypotension, which were increased in the GTN group. There did not appear to be a differential effect between patients with ischemic stroke and those with hemorrhagic stroke.

On possible reasons why no effect of GTN was seen, Professor Bath suggested that treatment may have been too late: The median time to treatment was 26 hours after symptom onset. In contrast, INTERACT-2 (Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial-2) suggested a benefit of blood pressure lowering in patients with intracerebral hemorrhage who received medication within 6 hours of symptom onset.

Common Clinical Dilemma

On the second part of the trial evaluating stopping or continuing patients preexisting antihypertensive drugs, Professor Bath explained that this was a common clinical dilemma.

While high blood pressure is associated with poor outcomes, certain antihypertensive drug classes have shown poor outcomes in acute stroke. There is the thought that stopping antihypertensive medication temporarily may allow an increase in collateral perfusion and brain salvage and avoid the aspiration of tablets in unstable patients.

Results showed that stopping antihypertensive medication for 1 week led to an average 9.5/5.1-mmHg difference in blood pressure at day 7. This difference increased with the number of antihypertensive agents being taken.

Again the primary outcome — shift in mRS score at 90 days — was completely neutral (odds ratio, 1.05). But secondary analyses suggested more increases in pneumonia, disability, and cognitive impairment in patients continuing medication.

"It is always difficult in a trial when secondary outcomes are significant when the primary outcome is neutral," Professor Bath said. "But I think ENOS does give us some practical guidance on what to do with the half of acute stroke patients who were taking blood pressure–lowering medicines before they had a stroke."

Combining With COSSACS

He pointed out that the ENOS results were similar to the smaller COSSACS (Continue Or Stop post-Stroke Antihypertensives Collaborative Study), which also found a neutral result on this question. But COSSACS did not include any dysphagic patients.

Putting ENOS and COSSACS together, Professor Tom Robinson, University of Leicester, United Kingdom, said, "There is no evidence of significant benefit from continuing preexisting blood pressure medications in all patients immediately. Nonetheless, hypertension is the single most important risk factor in the prevention of recurrent stroke and both trials show significantly lower blood pressure in the continue arm at 7 days. Furthermore, for most patients there was no evidence of harm of continuing if the patient does not have dysphagia."

He concluded, "Continuation of blood pressure medication is relatively safe and restarting drugs after at least 24 hours is reasonable, as long as the swallow has been regained and the patient is neurologically stable."

Professor Robinson noted that an individual-patient meta-analysis of the 2 trials is planned to look at the effect of specific drug classes.

Further information on blood pressure in acute stroke will come from ENCHANTED (ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy), which is assessing intensive blood pressure lowering in the setting of thrombolysis, he added.

ENOS was funded by the United Kingdom Medical Research Council and received no commercial sponsorship.

XXIII European Stroke Conference (ESC). Presented May 7, 2014.

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