Degree and Timing of Intensive Blood Pressure Lowering on Hematoma Growth in Intracerebral Hemorrhage
Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial-2 Results
Background and Purpose—Degree and timing of blood pressure (BP) lowering treatment in relation to hematoma growth were investigated in the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial-2 (INTERACT2).
Methods—INTERACT2 was an international clinical trial of intensive (target systolic BP [SBP], <140 mm Hg) versus guideline-recommended (SBP, <180 mm Hg) BP lowering in 2839 patients within 6 hours of spontaneous intracerebral hemorrhage and elevated SBP (150–220 mm Hg), in which 964 had repeat cranial computed tomography at 24 hours. ANCOVA models assessed categories of SBP reduction and time to target SBP on 24-hour hematoma growth.
Results—Greater SBP reduction was associated with reduced hematoma growth (13.3, 5.0, and 3.0 mL for <10, 10–20, and ≥20 mm Hg, respectively; P trend<0.001). In the intensive treatment group (n=491), the least mean hematoma growth was in patients who achieved target SBP <1 hour (2.6 mL) versus to those in target at 1 to 6 (4.7 mL) and >6 hours (5.4 mL). The smallest mean absolute hematoma growth (2.0 mL) was in those achieving target SBP 5 to 8 times versus 3 to 4 (3.1 mL) and 0 to 2 times (5.2 mL).
Conclusions—Intensive BP lowering with greater SBP reduction, which is achieved quickly and maintained consistently, seems to provide protection against hematoma growth for 24 hours.
Elevated systolic blood pressure (SBP) is common after acute spontaneous intracerebral hemorrhage (ICH). Attenuation of hematoma growth is the most plausible mechanism for any beneficial effect of intensive BP lowering, but this was not confirmed in the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT),1,2 leaving uncertainty over any heterogeneity of the treatment by timing and degree of BP lowering. We assessed the effects of degree and consistency of BP lowering on hematoma growth in INTERACT2 participants.
Materials and Methods
INTERACT2 was an international, multicenter, open, blinded end point, randomized controlled trial, as described elsewhere.2 In brief, 2839 spontaneous ICH patients (<6 hours of onset) and elevated SBP (150–220 mm Hg) were randomly assigned to intensive (target SBP, <140 mm Hg within 1 hour) or guideline-recommended (target SBP, <180 mm Hg) BP lowering.3 The study is registered with ClinicalTrials.gov, number NCT00716079.
Demographic and clinical characteristics were recorded, including SBP every 15 minutes in the first hour post randomization and 6 hourly until 24 hours; the number of readings <140 mm Hg were noted. In a substudy, baseline and 24±3-hour computed tomographic brain scans were performed and analyzed centrally.
ANCOVA models assessed associations of SBP reduction on 24-hour hematoma growth.
Among 2839 participants of the INTERACT2 study, 964 (40%) were included in the computed tomographic substudy. Compared with patients without a follow-up computed tomography, they were more often on anticoagulation or antiplatelet therapy, had higher National Institute of Health Stroke Scale scores, and shorter time from symptoms onset to randomization at baseline (Table I in the online-only Data Supplement). However, the 2 groups were similar with regard to baseline SBP, ICH volume and location, and allocation to intensive BP-lowering treatment. Table II in the online-only Data Supplement shows the patient characteristics by the degree of SBP reduction: those with the smallest ΔSBP (<10 mm Hg) were older and those with greatest ΔSBP (≥20 mm Hg) were more often women, with a history of ICH, higher baseline BP, and more often included to intensive BP-lowering group (420 [59%]; P<0.001). A greater degree of SBP reduction was associated with less hematoma growth: ∆SBP1–24 h at <10-, 10- to 20-, and ≥20-mm Hg reduction was associated with hematoma growth (mL) of 13.3 (9.0–17.5), 5.0 (1.6–8.4), and 3.0 (0.5–5.4), respectively (P trend<0.001). A similar trend was observed for the same degrees of ∆SBP15–60 mol/L, but this was not statistically significant (Figure 1). There was no significant difference in the relation of SBP reduction and hematoma growth in patients with baseline SBP levels above or below 180 mm Hg for any of ∆SBP1–24 h or ∆SBP15–60 mol/L (P homogeneity=0.133 and 0.999, respectively; Table III in the online-only Data Supplement). The results were similar in a sensitivity analysis stratified for trial treatment without any heterogeneity (Table IV in the online-only Data Supplement).
Table V in the online-only Data Supplement shows the participants’ baseline characteristics, which are grouped by time from symptom onset to randomization and were broadly similar between groups, except more patients allocated intensive treatment were on anticoagulation in at 3 to 4.5 hours. There was no association of intensive treatment with hematoma growth in these subgroups by time to treatment in crude or adjusted models (P trend=0.691 and 0.702, respectively; Figure 2; Table VI in the online-only Data Supplement).
Of 491 patients randomized to intensive BP lowering, the SBP target was achieved in 242 (49%) and 125 (25%) <1 and 1 to 6 hours, respectively; 124 (25%) did not achieve target <6 hours. The least hematoma growth (mL) was in those achieving target SBP early (≤1 hour; 2.6; 95% confidence interval, 0.1–5.2) compared with later periods 1 to 6 hour (4.7; 95% confidence interval, 1.8–7.5) and >6 hours (5.4; 95% confidence interval, 2.4–8.3; P trend=0.029; Figure 3A).
Hematoma growth was 5.2 (95% confidence interval, 2.7–1.8), 3.1 (0.3–6.0), and 0.4 (–1.1 to 5.1), respectively, according to 0 to 2, 3 to 4, and 5 to 8 times to target SBP (P trend=0.018; Figure 3B).
These analyses of INTERACT2 show that a greater fall in SBP was associated with less hematoma growth, irrespective of whether patients received intensive or guideline-based BP-lowering treatment. Patients with the least hematoma growth were those who achieved target SBP of <140 mm Hg within the first hour and in those who sustained this target throughout the first 24 hours. These data are relevant for patient management, where early, intensive, and consistent lowering of SBP seems to offer the greatest potential to improve outcome in ICH, including better functional recovery in those with smooth BP control.4 These results also support recent guideline recommendations for more intensive BP management in ICH.
Outcome in ICH depends on the size and growth of the underlying hematoma,5,6 which are related to mechanisms of intravascular hydrostatic pressure, local tissue pressure, and mechanical injury to brain tissue and blood vessels, cerebral blood flow, plasma protein induction, and inflammation.7,8 Other important factors that may influence hematoma growth include timing of imaging and baseline hematoma volume. Greater SBP reduction and shorter time to target SBP being associated with the least hematoma growth could be related to intensive BP lowering producing larger and faster decreases in intravascular hydrostatic pressure secondary arteriolar rupture. This analyses could not confirm the other mechanisms stated above. Our earlier analyses have shown a linear relationship between achieved SBP and disability in both the hyperacute (1–24 hours) and acute (2–7 days) phases,9 and similar findings have been reported in other populations.10,11
Although our study included a large and heterogeneous population with rigorous prospective and systematic evaluations of both BP and hematoma growth, the analyses are limited by selection bias, inability to establish a causal relationship with treatment, and in being post hoc and not prespecified.
In conclusion, these analyses suggest potential beneficial effects of early and controlled BP-lowering treatment through attenuation of hematoma growth.
C. Carcel, X. Wang, S. Sato, C. Stapf, and C.S. Anderson contributed to the concept of the study. S. Sato and C. Delcourt undertook the computed tomographic scan analysis. X. Wang contributed to statistical analysis. All authors participated in interpreting results, drafting and approval of the final article, and take responsibility for the content of this article.
Sources of Funding
The Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial-2 (INTERACT2) was supported by program (571281) and project grants (512402 and 1004170) from the National Health and Medical Research Council of Australia.
C.S. Anderson was supported by The George Institute for Global Health (TGI), holds a senior principal research fellowship, received National Health and Medical Research Council grants, reports membership of advisory boards for Astra Zeneca and Medtronic, and received travel reimbursement and honorarium from Takeda China. J. Chalmers received research grants from Servier, administered through the University of Sydney, as principal investigator for the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial and ADVANCE-Observational (ADVANCE-ON) post-trial study, and received honoraria from Servier for speaking about those studies at scientific meetings. P. Lavados has received a research grant from TGI.
*A list of all INTERACT2 study participants is given in online-only Data Supplement.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.116.013326/-/DC1.
- Received March 1, 2016.
- Revision received March 1, 2016.
- Accepted March 21, 2016.
- © 2016 American Heart Association, Inc.
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