Spontaneous supratentorial intracerebral hemorrhage (ICH) affects 4 million patients worldwide each year.1,2 Although this is a heterogeneous disorder with a wide range of outcomes, overall mortality at 1 month is ≈40%, and only 25% of patients have a favorable outcome.1,2 Acute hypertension is patients with ICH is common and may be linked to hematoma growth, cerebral edema, and poor outcome.3,4 Precise blood pressure guidelines and timing of implementation remain unclear.
In the second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2), patients with spontaneous ICH who had a systolic blood pressure of 150 to 220 mm Hg within 6 hours after symptom onset were randomly assigned to intensive treatment to lower their blood pressure (with a target systolic level of <140 mm Hg within 1 hour) or guideline-recommended treatment (with a target systolic level of <180 mm Hg) with the use of agents of the physician’s choosing.5 Among the 2794 participants for whom the primary outcome could be determined, 719 of 1382 participants (52.0%) receiving intensive treatment, compared with 785 of 1412 (55.6%) receiving guideline-recommended treatment, had a primary outcome event (death or major disability; odds ratio with intensive treatment, 0.87; 95% confidence interval [CI], 0.75-1.01; P = .06). The ordinal analysis showed significantly lower modified Rankin Scale scores with intensive treatment (odds ratio for greater disability, 0.87; 95% CI, 0.77-1.00; P = .04). Mortality was 11.9% in the group receiving intensive treatment and 12.0% in the group receiving guideline-recommended treatment. Nonfatal serious adverse events occurred in 23.3% and 23.6% of the patients in the 2 groups, respectively.
Critics of the trial noted that a greater effect might not have been realized because hematoma expansion and the rate of subsequent death or disability might be decreased with earlier and more aggressive reduction in blood pressure in high-risk patients with blood pressure levels >180 mm Hg (10-11). Recently, the results of the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-2) trial were published in the New England Journal of Medicine.6 The goal was to assess whether rapid lowering of systolic blood pressure level in patients in an earlier time window after symptom onset than that evaluated in previous trials leads to better outcomes.4,5
In this multicenter trial, patients with ICH (volume <60 cm3) and a Glasgow Coma Scale score of ≥5 were randomized to a systolic blood pressure target of 110 to 139 mm Hg (intensive treatment) or a target of 140 to 179 mm Hg (standard treatment) to test the superiority of intensive reduction of systolic blood pressure to standard reduction.6 Intravenous nicardipine to lower blood pressure was administered within 4.5 hours after symptom onset. The primary outcome was death or disability (modified Rankin Scale score, 4-6) at 3 months after randomization as ascertained by an investigator who was blinded to the treatment assignments.
Among 1000 participants with an approximate mean systolic blood pressure of 200 mm Hg at baseline, 500 were assigned to intensive treatment and 500 to standard treatment. The mean age of the patients was 62 years, and 56% were Asian. Enrollment was stopped because of futility after a prespecified interim analysis. There was no significant difference in the incidence of the primary outcome of death or disability in the intensive-treatment group (186 of 481, 38.7%) vs the standard-treatment group (181 of 480, 37.7%). Adjustment for potential independent risk factors, including age, initial Glasgow Coma Scale score, and presence or absence of intraventricular hemorrhage, did not alter these results (relative risk, 1.04; 95% CI, 0.85-1.27). Serious adverse events occurring within 72 hours after randomization that were considered by the site investigator to be related to treatment were reported in 1.6% of the patients in the intensive-treatment group and in 1.2% of those in the standard-treatment group. Importantly, the rate of renal adverse events within 7 days after randomization was significantly higher in the intensive-treatment group (9.0%) than in the standard-treatment group (4.0%).
There are a number of key differences between the INTERACT2 trial5 and the ATACH-2 trial.6 An estimated 41% of the participants in INTERACT2 underwent randomization ≥4 hours after symptom onset, whereas all participants in the ATACH-2 trial underwent randomization and were treated within 4.5 hours after symptom onset. Similarly, only a fraction of patients in INTERACT2 underwent randomization with an initial systolic blood pressure of ≥180 mm Hg vs all patients in the ATACH-2 trial. Additionally, treatment failure in the intensive cohorts was much more common in INTERACT2 (66%) vs ATACH-2 (12.2%). Mean systolic blood pressures in the first 2 hours after randomization were significantly lower in the ATACH-2 trial vs the INTERACT2 trial.
Thus, the present trial does not support an aggressive protocol of systolic blood pressure lowering in the setting of ICH. A number of areas remain unclear, including the optimal targeting of blood pressure in these patients and the timing of achieving this goal. Furthermore, the results of this trial cannot be extended to patients with large ICHs, significant elevations in intracranial pressure, or altered cerebral perfusion pressure. Further studies are needed to define the best blood pressure management in these patients. Although the optimal goal is still a matter of debate and may need to be titrated on the basis of patient- and ICH-specific parameters, systolic blood pressures of 140 to 180 mm Hg would be a reasonable goal until we have firmer evidence.
1. van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010;9(2):167–176.
2. Feigin VL, Lawes CM, Bennett DA, Anderson CS. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol. 2003;2(1):43–53.
3. Qureshi AI. The importance of acute hypertensive response in ICH. Stroke. 2013;44(6 suppl 1):S67–S69.
4. Anderson CS, Huang Y, Arima H, et al. Effects of early intensive blood pressure-lowering treatment on the growth of hematoma and perihematomal edema in acute intracerebral hemorrhage: the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT). Stroke. 2010;41(2):307–312.
5. Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med. 2013;368(25):2355–2365.
6. Qureshi AI, Palesch YY, Barsan WG, et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. N Engl J Med. 2016;375(11):1033–1043.