Intensive lowering of BP unrelated to stroke recovery

HONOLULU – While intensive lowering of blood pressure may reduce the risk of intracerebral hemorrhage (ICH) following thrombolytic therapy for acute ischemic stroke (AIS), the protocol does not improve post stroke recovery, according to new research.

As part of the International Open Trial (ENCHANTED) on Enhanced Control of Hypertension and Thrombolysis, the researchers recruited more than 2,000 patients (74% recruited from Asia) and badigned them to randomly to one of the two BP management groups less than 6 hours after the start of stroke.

The improvement in functional status at 90 days, measured by the modified Rankin Scale scores (mRS), did not differ between the group badigned to the lowering of the intensive systolic pressure (AS) from 130 to 140 mmHg in less than an hour and that badigned to a standard, recommended target of less than 180 mmHg over 72 hours, according to recommendations. This meant that the test had not achieved its primary goal of effectiveness.

The key secondary outcome of the safety was any intracranial hemorrhage reported; the rate of these hemorrhages was significantly lower in the intensive group (14.8% versus 18.7%, respectively).

"This study clearly shows that an intensive lowering of blood pressure could make treatment of thrombolysis safer by reducing the risk of serious cerebral hemorrhage," said lead researcher Craig Anderson, MD, Ph. D., Professor of Neurology at the University of New South Wales, Sydney, Australia, who is executive director of the George Institute China in Beijing, said in a press release. But he noted that more research is needed to determine why this risk reduction did not translate into an improvement in the overall result.

"The main result was neutral, which was a little disappointing, because it indicates that your recovery is not generally improved, but it also tells you that it is safe because it does not aggravate patients" said Anderson. Medscape Medical News.

The findings of the ENCHANTED Blood Pressure Intensity Group were presented at a last-minute scientific session held here at the International Stroke Conference (ISC) 2019 and have were simultaneously published online on 7 February in the Lancet.

Controversial area

Observational studies have shown a link between high blood pressure and poor results. In addition, high blood pressure in the setting of thrombolysis increases the risk of PCI.

BMS greater than 185 mmHg "is a contraindication to intravenous thrombolytic therapy with intravenous alteplase" for patients with AIS, the researchers write. However, the target level of SBP for an optimal outcome is "uncertain".

"This is one of the most controversial areas of stroke medicine, and people have been talking about it for years and years," Anderson said. "The long-standing recommendation was that you have to be very careful about controlling blood pressure in stroke patients because the brain is damaged, circulation in the brain is already compromised."

He added that a threshold had been set in a test for tissue plasminogen activator (APT) published in 1995. "And that has always been the gospel – this blood pressure should be at 180 ° C. However, there is evidence of bleeding and poor outcomes to determine if a more intensive diet could offer patients better results than the long-standing gospel of a higher threshold, "Anderson said.

In ENCHANTED, 2227 patients eligible for alteplase (62% male, 73.7% of Asian origin, 66.9 years of age) with AIS in 110 hospitals of 15 Countries were recruited from March 2012 to April 2018. Initially, all patients had suffered moderate moderate-severity stroke, as defined by a score of 7 on the National Institutes of Health scale.

Of the 2196 participants included in the badyzes, 1081 were randomly badigned to the intensive group. For these patients, the SBP objective was less than 130-140 mmHg in one hour; SBP was then maintained for up to 72 hours with locally available agents. The standard management group included 1115 patients. For these patients, the target PAS was less than 180 mmHg over 72 hours. The mean PAS before treatment was 165 mmHg and the median time from onset to randomization was 3.3 hours.

The study used a prospective, randomized, open-minded, and blind (PROBE) design, reported Anderson.

No greater than guideline recommendations

The results showed that the average 24-hour PAS was 144.3 mmHg for the intensive group versus 149.8 mmHG for the standard group. Although this resulted in a statistically significant difference (P <0.0001), it did not reach the expected difference of 15 mmHg.

There was no significant difference between groups in improving mRS (odds ratio) scores. [OR]1.01; 95% confidence interval [CI]0.87 to 1.17; P = 0.87).

The researchers also evaluated "a number of predefined subgroups." There was no significant heterogeneity in the primary endpoint for age-related badessment. 39, ethnicity, baseline systolic blood pressure, ischemic stroke subtype and dose ", Thompson G. Robinson, lead author, Leicester Biomedical Research Center of the National Research Institute of Health, Glenfield Hospital, United Kingdom, told attendees at the meeting.

However, there were significantly fewer cases of intracranial hemorrhage in the intensive group (OR, 0.75, 95% CI, 0.60 to 0.94; P = 0.014). There were also significantly fewer reports of intracranial hemorrhage as a serious adverse event, including a significant PCI, in the intensive group (5.5% vs. 9.0%; OR, 0.59%). ; P = 0.002).

"There was a clear signal that it was reducing the bleeding – it's the most disturbing thing about thrombolysis, and it's one of the biggest hurdles that has kept us from developing a bleeding." thrombolysis because of the adverse effects of the treatment, "said Anderson.

There were no significant differences in other outcomes of efficacy and safety, including death and neurological decline.

Overall, a drop in intensive blood pressure "did not prove to be superior to the recommended blood pressure reduction by recommendation for the primary disability outcome, and there was consistent neutral results in all prespecified subgroups ", summarized Robinson. The protocol, however, showed that it was safe with respect to mRS scores, reports of serious adverse events and reduced risk of intracranial hemorrhage, he added.

Robinson pointed to several possible reasons why an intensive reduction in blood pressure did not improve the main result. These include the fact that there were "challenges" with the protocol used for the intensive group; that there was only a small difference in SBP between groups; that there was little significant PCI; and that there may have been some bias due to the open design of the study.

In addition, he asked if the fact that the majority of their participants were Asian could have affected the results. "Questions may arise about the possibility of generalization.Although it has been suggested that there is no heterogeneity according to ethnicity, the population Asian could be at higher risk due to intracranial atheroma and a small vessel brain disease, "he said.

"ENCHANTED has not completely resolved the uncertainty about the optimal level of blood pressure control and the approach we should use to improve recovery," Robinson said. "We certainly wish to continue researching our extensive brain imaging database to understand why this reduction in hemorrhage has not globally translated into better recovery."

"Disenchanting" evidence?

In an accompanying editorial, Else Charlotte Sandset, MD, PhD, Department of Neurology at the University Hospital of Oslo, Norway, and Urs Fischer, MD, Department of Neurology at the University of New York. University Hospital Bern, Switzerland, write that ENCHANTED is the first large-scale trial to evaluate the control of blood pressure in the context of thrombolysis IV for AIS "and adds important evidence" that a control Intensive blood pressure reduces intracranial hemorrhage, but is not badociated with improved recovery of stroke.

"This finding could be related to the difference in blood pressure between the groups below that considered, or to the inclusion of patients with mild to moderate stroke, who are less likely to develop symptomatic intracerebral hemorrhage" they write.

"However, this new evidence is somewhat disenchanted.As with other large-scale trials, ENCHANTED has shown a neutral effect of lowering blood pressure on functional outcome in acute stroke" they add.

Editorialists note that one of the reasons for this effect could be that the goal of lowering blood pressure was too low, "causing hypoperfusion in the intensive treatment group and neutralizing the favorable outcomes resulting from 39, a reduction in intracranial hemorrhage ". They also cite the general inclusion criteria of the test as a possible limitation.

"The selection of patients for the treatment of stroke is becoming increasingly important, several trials that used a unique concept for all patients have not shown the benefits of treatment," write Sandset and Fischer . Instead, pathophysiological considerations should be used when selecting study participants, they add.

"As clinicians, we are treating people: it is therefore necessary to have more evidence for individualized treatment approaches," and the use of advanced imaging should be used in future studies. in order to better understand the underlying mechanisms of the advantages or disadvantages of treatment, "editorialists explain. to write.

The advantage does not translate into results

Invited to comment, Ralph Sacco, MD, former president of the American Heart Association and current president of the American Academy of Neurology, said Medscape Medical News it was an interesting trial evaluating blood pressure lowering strategies "in all patients treated with tPA intravenously".

Although there was no difference in the main result between the groups, "the group treated by the guidelines was treated more aggressively than usual for blood pressure" said Sacco, also a professor and chair of neurology at the Miller School of Medicine, Florida. He was not involved in the ongoing research.

"Normally, we try to reduce the systolic blood pressure to about 180 [mmHg]but in the end, the reference group arrived at around 150, and the intense group, around 144. So there is only a difference of 6 mm, "he added.

He also noted "less cerebral bleeding" in the intense group. "This will not change the guidelines, and if so, it suggests that people are already more aggressive in controlling their blood pressure for people about to receive intravenous tPA.

"We are still trying to push the needle and, especially in the acute phase of stroke, we are asking: is it safe and is it more effective? I think that here we are talking now blood pressure to 150, and 130 to 140 And maybe if you lower your blood pressure a little better, you reduce the risk of cerebral hemorrhage, which is important, "Sacco said.

"There was therefore a benefit in terms of bleeding, but that did not translate into a 90-day disability difference, which is really the end result of this trial," he said. he adds.

The study was funded primarily by the Australian Council of Health and Medical Research (NHMRC) and the UK Stroke Association. Anderson has received grants from NHMRC Australia and Takeda China, as well as fees for Boehringer Ingelheim and Amgen Advisory Board activities, as well as Takeda's speaker fees. The original articles contain a complete list of disclosures made by other study writers and editorial writers. Sacco has not reported any relevant financial relationship.

International Stroke Conference (ISC), 2019. Summary LB6. Presented on February 7, 2019.

Lancet. Posted online February 7, 2019. Abstract, Editorial

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