June 2013 - Article of the Month Podcast #2
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Patients with hemorrhagic stroke, or intracerebral hemorrhage (ICH), are common in emergency medicine and frequently present to the emergency department with significantly elevated blood pressures requiring urgent treatment. The correct goal blood pressure is debatable. On one hand there is concern that the hydrostatic effects of elevated blood pressure could contribute to expansion of the hematoma, increased edema, or rebleeding. On the other hand, overcorrection of the blood pressure could lead to decreased cerebral perfusion in the setting of autoregulation.
Currently, the AHA/American Stroke Association recommendations for the management of blood pressure in spontaneous (atraumatic) ICH are as follows:
1) If SBP is > 200 mmHg or MAP is >150 mmHg, then consider aggressive reduction of BP with continuous intravenous infusion.
2) If SBP is >180 mmHg or MAP is >130mm Hg and there is the possibility of elevated ICP, then consider monitoring ICP and reducing BP using intermittent or continuous intravenous medications while maintaining a cerebral perfusion pressure >60 mmHg.
3) If SBP is >180 mmHg or MAP is >130 mmHg and there is no evidence of elevated ICP, then consider a modest reduction of BP (e.g. MAP of 110 mmHg or target BP of 160/90 mmHg) using intermittent or continuous intravenous medications to control BP.
4) In patients presenting with a systolic BP of 150 to 220 mmHg, acute lowering of systolic BP to 140 mm Hg is probably safe
Note that these recommendations are Class C, based partly on the INTERACT pilot study, which looked at 440 patients and compared goal SBP of 140 mmHG with more modest reductions to 180 mmHG. They found a trend toward reduced hematoma growth with no increase in neurologic deterioration or differences in other clinical outcomes (disability, quality of life). The study was underpowered to detect significant differences in any of the outcomes.
INTERACT2 was an international, multicenter, prospective, randomized trial. The study was open-treatment by necessity; patients and providers could not be blinded to group allocation due to the nature of the study. They were blinded to the end-point of the trial, and outcome assessors were blinded to group allocation. Patients were excluded if they had a definite contraindication to BP-lowering treatment, if treatment could not be initiated within 6 hours of ICH, if there was a structural cause for the ICH, if they had a GCS of 3-5 (“deep coma”), if they had a massive hematoma with poor prognosis, or if early surgical evacuation of the hematoma was planned.
Patients were randomized to two groups: 1) in the intensive-treatment group, IV and oral antihypertensive were initiated by protocols based on the local availability of agents, with the goal of achieving a SBP < 140 mmHg within one hour of randomization and maintaining this level for 7 days; 2) in the standard-treatment group, BP-lowering treatment was initiated if the SBP was > 180 mmHg, with no lower level stipulated. All patients were started on oral antihypertensives within 7 days or hospital discharge. Patients were followed-up in person of by telephone at 28 days and 90 days by local staff blinded to treatment group. Patients were analyzed by the intention to treat principle.
The primary outcome was the proportion of patients with a poor outcome: death or severe disability (a score of 3-5 on the modified Rankin scale at 90 days after randomization). Initially, the key secondary outcome was death or severe disability in patients in whom treatment was initiated within 4 hours of onset of ICH. This was changed prior to data analysis to physical function across all 7 levels of the modified Rankin scale using ordinal analysis. Other secondary outcomes included: all-cause mortality; cause-specific mortality; health related quality of life; duration of hospitalization; residence at a residential care facility at 90 days; poor outcomes at 7 and 28 days; and serious adverse events (neurologic deterioration or severe hypotension). They also assessed change in hematoma size in a subset of patients who underwent repeat CT or MRI at 24 hours post-ICH.
Between October 2008 and August 2012, 2839 patients were enrolled at 144 hospitals in 21 countries; 1403 were assigned to intensive-treatment and 1436 were assigned to standard treatment. Patients were similar with respect to known risk factors…with the exception of warfarin use (3.6% in the intensive-treatment group, 2.2% in the standard-treatment group, p = 0.025). Approximately 68% of all patients were recruited from Chinese hospitals. In terms of treatment, patients in the intensive-treatment group received antihypertensives more quickly and had more rapid lowering of BP than those in the standard-treatment group. Of note, patients in the intensive-treatment group were more likely to have care withdrawn than those in the standard-treatment group (5.4% vs. 3.3%, p = 0.005). The primary outcome was assessed in 98.5% of intensive-treatment patients and 98.3% of standard-treatment patients.
For the primary outcome, poor outcome at 90 days (death or score of 3-5 on the modified Rankin scale), there was no difference between the intensive-treatment (52%) and standard-treatment (55.6%) groups (OR 0.87; 95% CI 0.75-1.01). Ordinal analysis showed a favorable shift in the distribution of scores on the modified Rankin scale for patients in the intensive-treatment group (pooled OR for a shift to higher score of 0.87, 95% CI 0.77-1.00). The rate of death from any cause was similar for the intensive-treatment and standard treatment group (11.9% vs. 12.0% (OR 0.99; 95% CI 0.79-1.25) as was the percentage of deaths directly attributed to the ICH, duration of hospitalization, and rates of serious adverse events.
Patients in the intensive-treatment group reported better quality of life at 90 days using the European QOL 5-dimension questionnaire which assesses mobility, self-care, usual activities, pain or discomfort, and anxiety or depression (each graded on a 3-level scale as either no problems, moderate problems, or extreme problems) than those in the standard-treatment group: mean utility score 0.6 vs. 0.55. p = 0.002.
For patients who underwent repeat brain imaging at 24 hours (35.1% of the intensive-treatment group and 33.1% of the standard-treatment group) there was no significant difference in the mean hematoma growth: relative difference 4.5% (95% CI -3.1% to 12.7%), absolute difference 1.4 mL (95% CI -0.6 mL to 3.4 mL).
The authors note that while intensive lowering of BP in ICH did not result in a significant reduction in the primary outcome, there were better functional outcomes when an ordinal analysis of the primary outcome was undertaken. The ordinal analysis showed a very slight benefit with intensive lowering of BP, with a 95% CI that just reaches 1.00 (and a p-value of 0.04). Keep in mind that the authors chose to perform ordinal analysis after the data had been collected. One should always beware when investigators change the study in some way after data collection has been initiated. In this case, the authors’ reasoning was that ordinal analysis began gaining acceptance in clinical trials partway through the course of the trial. Also keep in mind that this is the secondary outcome, not the primary outcome, which was selected a priori. For the other secondary outcome of quality of life, there was a slight improvement with intensive lowering of BP with a mean EQ-5D score of 0.6 vs. 0.55. The clinical significance of this difference is unfortunately difficult to interpret. If my overall score is 0.6, how much better off am I than someone with a score of 0.55?
Issues of external validity have been raised as well, given that the majority of patients in the study (68%) were recruited from Chinese institutions. We have to ask two questions: 1) are Chinese patients with ICH somehow different than patients in our own institutions? and 2) is the treatment of ICH in Chinese institutions different than treatment at our institutions? Given that the majority of patients with spontaneous ICH are treated with supportive care, and that the indications for invasive procedures (ICP monitoring, craniotomy/craniectomy) are likely the same at any large hospital with neurosurgical capability, I would suspect that these results are likely valid in the US. Additional studies at US institutions may help elucidate this further.
The authors conclude: “early intensive lowering or BP in this patient population is safe,” which is in keeping with the AHA/ASA guidelines, which state “In patients presenting with a systolic BP of 150 to 220 mmHg, acute lowering of systolic BP to 140 mm Hg is probably safe.” I tend to agree with these statements. This study alone should by no means make intensive lowering of BP in ICH standard of care, as there is no clear benefit.
The authors in this study used an ordinal analysis of the modified Rankin score. The Rankin score is an example of a type of categorical data known as ordinal data, in which numerical scores are arbitrarily assigned to levels of measurement. The assigned number itself has no meaning, other than to provide a scale for reference. Examples include pain scores (0 out of 10 means no pain, 10 out 10 is severe pain). Classically, studies that look at outcomes based on ordinal data have applied a cutoff, thus turning a scale with multiple levels into a binary outcome. Instead of worrying about whether you’re a 1, 2, 3, etc., we only care about whether you’re above or below the cutoff. We can then compare the proportions above or below the cutoff in 2 groups and assign p-values or chi-square values. Ordinal analysis on the other hand uses more complex statistical calculations to assess shifts across the entire spectrum of the scale. This has been shown to have higher statistical power than using binary outcomes alone.