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Deferoxamine in intracerebral hemorrhage: Systematic review and meta-analysis
Sun T, Zhao YY, Xiao QX, Wu M, Luo MY
Clinical neurology and neurosurgery. 2023;227:107634
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Editor's Choice
Abstract
BACKGROUND Intracerebral hemorrhage (ICH) is a stroke with a high morbidity and mortality rate. Deferoxamine (DFX) is thought to be effective in treating Intracerebral Hemorrhage. In our study, we performed a meta-analysis to evaluate the treatment effects of DFX. METHODS We systematically searched PubMed, Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Chinese Biomedical Literature Database in Jan 2022 for studies on DFX for ICH patients. Outcome measures included relative hematoma volume, relative edema volume, good neurological functional outcome and adverse events. Odds risk (OR) and weighted mean difference (WMD) were used to evaluate clinical outcomes. RESULTS After searching 636 articles, 4 RCTs, 2 NRCTs, and 1cohort study were included. We found that DFX was effective in hematoma absorption on day 7 after onset, but the difference was not significant on day 14. DFX could suppress edema expansion on days 3, 7, and 14 after onset. DFX did not contribute to better outcomes after 3 and 6 months when used the modified Rankin Scale and the Glasgow Outcome Scale to evaluate neurological prognosis. The pooled results showed no statistically significant difference in Serious adverse events between the experimental and control groups. CONCLUSIONS DFX could limit edema expansion on days 3, 7, and 14 after commencement and facilitate hematoma absorption at week 1 without significantly increasing the risk of adverse events, but it did not improve neurological prognosis.
PICO Summary
Population
Patients with intracerebral haemorrhage (n= 7 studies).
Intervention
Deferoxamine (DFX).
Comparison
Placebo.
Outcome
Outcome measures included relative haematoma volume, relative oedema volume, good neurological functional outcome and adverse events. DFX was effective in haematoma absorption on day 7 after onset, but the difference was not significant on day 14. DFX could suppress oedema expansion on days 3, 7, and 14 after onset. DFX did not contribute to better outcomes after 3 and 6 months when used the modified Rankin Scale and the Glasgow Outcome Scale to evaluate neurological prognosis. The pooled results showed no statistically significant difference in serious adverse events between the experimental and control groups.
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Efficacy and safety of tranexamic acid in intracranial haemorrhage: A meta-analysis
Xiong Y, Guo X, Huang X, Kang X, Zhou J, Chen C, Pan Z, Wang L, Goldbrunner R, Stavrinou L, et al
PloS one. 2023;18(3):e0282726
Abstract
BACKGROUND Although some studies have shown that tranexamic acid is beneficial to patients with intracranial haemorrhage, the efficacy and safety of tranexamic acid for intracranial haemorrhage remain controversial. METHOD The PubMed, EMBASE, and Cochrane Library databases were systematically searched. The review followed PRISMA guidelines. Data were analyzed using the random-effects model. RESULTS Twenty-five randomized controlled trials were included. Tranexamic acid significantly inhibited hematoma growth in intracranial hemorrhage (ICH) and traumatic brain injury (TBI) patients. (ICH: mean difference -1.76, 95%CI -2.78 to -0.79, I2 = 0%, P < .001; TBI: MD -4.82, 95%CI -8.06 to -1.58, I2 = 0%, P = .004). For subarachnoid hemorrhage (SAH) patients, it significantly decreased the risk of hydrocephalus (OR 1.23, 95%CI 1.01 to 1.50, I2 = 0%, P = .04) and rebleeding (OR, 0.52, 95%CI 0.35 to 0.79, I2 = 56% P = .002). There was no significance in modified Rankin Scale, Glasgow Outcome Scale 3-5, mortality, deep vein thrombosis, pulmonary embolism, or ischemic stroke/transient ischemic. CONCLUSION Tranexamic acid can significantly reduce the risk of intracranial haemorrhage growth in patients with ICH and TBI. Tranexamic acid can reduce the incidence of complications (hydrocephalus, rebleeding) in patients with SAH, which can indirectly improve the quality of life of patients with intracranial haemorrhage.
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Tranexamic Acid for Intracerebral Hemorrhage in Patients on Non-Vitamin K Antagonist Oral Anticoagulants (TICH-NOAC): A Multicenter, Randomized, Placebo-Controlled, Phase 2 Trial
Polymeris, A. A., Karwacki, G. M., Siepen, B. M., Schaedelin, S., Tsakiris, D. A., Stippich, C., Guzman, R., Nickel, C. H., Sprigg, N., Kägi, G., et al
Stroke. 2023
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Abstract
BACKGROUND Evidence-based hemostatic treatment for intracerebral hemorrhage (ICH) associated with non-vitamin K antagonist oral anticoagulants (NOACs) is lacking. Tranexamic acid (TXA) is an antifibrinolytic drug potentially limiting hematoma expansion. We aimed to assess the efficacy and safety of TXA in NOAC-ICH. METHODS We performed a double-blind, randomized, placebo-controlled trial at 6 Swiss stroke centers. Patients with NOAC-ICH within 12 hours of symptom onset and 48 hours of last NOAC intake were randomized (1:1) to receive either intravenous TXA (1 g over 10 minutes followed by 1 g over 8 hours) or matching placebo in addition to standard medical care via a centralized Web-based procedure with minimization on key prognostic factors. All participants and investigators were masked to treatment allocation. Primary outcome was hematoma expansion, defined as ≥33% relative or ≥6 mL absolute volume increase at 24 hours and analyzed using logistic regression adjusted for baseline hematoma volume on an intention-to-treat basis. RESULTS Between December 12, 2016, and September 30, 2021, we randomized 63 patients (median age, 82 years [interquartile range, 76-86]; 40% women; median hematoma volume, 11.5 [4.8-27.4] mL) of the 109 intended sample size before premature trial discontinuation due to exhausted funding. The primary outcome did not differ between TXA (n=32) and placebo (n=31) arms (12 [38%] versus 14 [45%]; adjusted odds ratio, 0.63 [95% CI, 0.22-1.82]; P=0.40). There was a signal for interaction with onset-to-treatment time (P(interaction)=0.024), favoring TXA when administered within 6 hours of symptom onset. Between the TXA and placebo arms, the proportion of participants who died (15 [47%] versus 13 [42%]; adjusted odds ratio, 1.07 [0.37-3.04]; P=0.91) or had major thromboembolic complications within 90 days (4 [13%] versus 2 [6%]; odds ratio, 1.86 [0.37-9.50]; P=0.45) did not differ. All thromboembolic events occurred at least 2 weeks after study treatment, exclusively in participants not restarted on oral anticoagulation. CONCLUSIONS In a smaller-than-intended NOAC-ICH patient sample, we found no evidence that TXA prevents hematoma expansion, but there were no major safety concerns. Larger trials on hemostatic treatments targeting an early treatment window are needed for NOAC-ICH. REGISTRATION URL: https://clinicaltrials.gov; Unique identifier: NCT02866838.
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The outcomes of combined endoscopic surgery and fibrinolytic treatment protocol for intraventricular hemorrhage: a randomized controlled trial
Noiphithak R, Ratanavinitkul W, Yindeedej V, Nimmannitya P, Yodwisithsak P
World neurosurgery. 2023
Abstract
BACKGROUND Intraventricular fibrinolysis (IVF) and endoscopic surgery (ES) are the new promising treatment strategies to enhance the rate of hematoma clearance which might improve functional outcome. This study investigated and compared the outcomes among these interventions. METHODS A randomized (1:1) double-blinded trial was carried out between August 2018 and December 2021. The intervention and control groups comprised patients receiving IVF and/or ES, and external ventricular drainage (EVD), respectively. All participants had experienced primary or secondary IVH from spontaneous intracerebral hemorrhage with obstructive hydrocephalus complications. The primary outcome was modified Rankin scale (mRS) score at 180 days post-treatment. Interim assessments were planned for every 50 participants enrolled to ensure safety and efficacy. RESULTS After enrollment of 110 participants (55 participants in each group), there was the difference in 30-day mortality (2 [3.6%] vs 13 [32.7%] in EVD group, p = 0.002), reaching the predetermined boundaries for the termination of the trial. We demonstrated a better favorable outcome (mRS 0-3) at 180 days in the intervention group, compared to control group (35 [63.6%] vs. 24 [43.6%], p = 0.04). Participants in the intervention group experienced a higher IVH removal rate (91% [9.0] vs. 69.5% [38.0], p < 0.01), and had lower shunt conversion (1 [1.8%] vs. 16 [29.3%], p < 0.01). Treatment complications were comparable between the two groups. CONCLUSIONS This study demonstrated that combined ES and IVF is safe and effective for the treatment of IVH. In addition, it concluded that aggressive but safe procedures used to remove IVH could improve clinical outcome in patients with IVH.
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Neuroendoscopic evacuation improves outcomes compared to external ventricular drainage in patients with spontaneous intraventricular hemorrhage: a systematic review with meta-analyses
Mezzacappa FM, Weisbrod LJ, Schmidt CM, Surdell D
World neurosurgery. 2023
Abstract
BACKGROUND Spontaneous intraventricular hemorrhage (IVH) is a cause of significant morbidity and mortality. Treatment for the resulting obstructive hydrocephalus has traditionally been via an external ventricular drain (EVD). We aimed to compare patient outcomes after neuroendoscopic surgery (NES) evacuation of IVH versus EVD management. METHODS MEDLINE, EMBASE, and the Cochrane Library were searched on October 8, 2022, with adherence to PRISMA guidelines. Of the 252 records remaining after removal of duplicates, 12 met the study's inclusion criteria. After extraction of outcomes data, fixed-effects and random-effects models were used to establish odds-ratios with 95% confidence intervals (CIs) for intensive care-unit (ICU) length-of-stay (LOS), rate of permanent cerebrospinal fluid (CSF) diversion, Glasgow Outcomes Scale (GOS) score, and mortality rate. RESULTS The results of the pooled analysis showed that ICU LOS was shorter (OR -2.61 [95% CI -5.02, -0.19]; I(2)=97.76%; p=0.034), permanent CSF diversion was less likely (OR -0.79 [95% CI -1.17, -0.41]; I(2)=46.96%; p<0.001), higher GOS was more likely (OR 0.48 [95% CI 0.04, 0.93]; I(2)=60.12%; p=0.032), and all-cause mortality was less likely (OR -1.11 [95% CI -1.79, -0.44]; I(2)=0%; p=0.001) in the NES evacuation group compared to the EVD group. CONCLUSIONS NES for evacuation of spontaneous IVH results in reduced ICU LOS, reduced permanent CSF diversion rates, improved GOS, and reduced mortality when compared with EVD. More robust prospective, randomized studies are necessary to help inform the safety and utility of NES for IVH.
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Time Course of Early Hematoma Expansion in Acute Spot-Sign Positive Intracerebral Hemorrhage: Prespecified Analysis of the SPOTLIGHT Randomized Clinical Trial
Al-Ajlan FS, Gladstone DJ, Song D, Thorpe KE, Swartz RH, Butcher KS, Del Campo M, Dowlatshahi D, Gensicke H, Lee GJ, et al
Stroke. 2023
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Editor's Choice
Abstract
BACKGROUND In the SPOTLIGHT trial (Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy), patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral hemorrhage were randomized to rFVIIa (recombinant activated factor VIIa; 80 μg/kg) or placebo within 6 hours of onset, aiming to limit hematoma expansion. Administration of rFVIIa did not significantly reduce hematoma expansion. In this prespecified analysis, we aimed to investigate the impact of delays from baseline imaging to study drug administration on hematoma expansion. METHODS Hematoma volumes were measured on the baseline CT, early post-dose CT, and 24 hours CT scans. Total hematoma volume (intracerebral hemorrhage+intraventricular hemorrhage) change between the 3 scans was calculated as an estimate of how much hematoma expansion occurred before and after studying drug administration. RESULTS Of the 50 patients included in the trial, 44 had an early post-dose CT scan. Median time (interquartile range) from onset to baseline CT was 1.4 hours (1.2-2.6). Median time from baseline CT to study drug was 62.5 (55-80) minutes, and from study drug to early post-dose CT was 19 (14.5-30) minutes. Median (interquartile range) total hematoma volume increased from baseline CT to early post-dose CT by 10.0 mL (-0.7 to 18.5) in the rFVIIa arm and 5.4 mL (1.8-8.3) in the placebo arm (P=0.96). Median volume change between the early post-dose CT and follow-up scan was 0.6 mL (-2.6 to 8.3) in the rFVIIa arm and 0.7 mL (-1.6 to 2.1) in the placebo arm (P=0.98). Total hematoma volume decreased between the early post-dose CT and 24-hour scan in 44.2% of cases (rFVIIa 38.9% and placebo 48%). The adjusted hematoma growth in volume immediately post dose for FVIIa was 0.998 times that of placebo ([95% CI, 0.71-1.43]; P=0.99). The hourly growth in FFVIIa was 0.998 times that for placebo ([95% CI, 0.994-1.003]; P=0.50; Table 3). CONCLUSIONS In the SPOTLIGHT trial, the adjusted hematoma volume growth was not associated with Factor VIIa treatment. Most hematoma expansion occurred between the baseline CT and the early post-dose CT, limiting any potential treatment effect of hemostatic therapy. Future hemostatic trials must treat intracerebral hemorrhage patients earlier from onset, with minimal delay between baseline CT and drug administration. REGISTRATION URL: https://www. CLINICALTRIALS gov; Unique identifier: NCT01359202.
PICO Summary
Population
Patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral haemorrhage (ICH) enrolled in the SPOTLIGHT trial (n= 50).
Intervention
Recombinant activated factor VIIa (n= 19).
Comparison
Placebo (n= 25).
Outcome
This prespecified analysis aimed to investigate the impact of delays from baseline imaging to study drug administration on haematoma expansion. Haematoma volumes were measured on the baseline CT, early post-dose CT, and 24 hours CT scans. Total haematoma volume (intracerebral haemorrhage + intraventricular haemorrhage) change between the 3 scans was calculated as an estimate of how much haematoma expansion occurred before and after studying drug administration. Of the 50 patients included in the trial, 44 had an early post-dose CT scan. Median time (interquartile range) from onset to baseline CT was 1.4 hours (1.2 - 2.6). Median time from baseline CT to study drug was 62.5 (55 - 80) minutes, and from study drug to early post-dose CT was 19 (14.5 - 30) minutes. Median (interquartile range) total haematoma volume increased from baseline CT to early post-dose CT by 10.0 mL (-0.7 to 18.5) in the rFVIIa arm and 5.4 mL (1.8 - 8.3) in the placebo arm. Median volume change between the early post-dose CT and follow-up scan was 0.6 mL (-2.6 to 8.3) in the rFVIIa arm and 0.7 mL (-1.6 to 2.1) in the placebo arm. Total haematoma volume decreased between the early post-dose CT and 24-hour scan in 44.2% of cases (rFVIIa 38.9% and placebo 48%). The adjusted haematoma growth in volume immediately post dose for FVIIa was 0.998 times that of placebo ([95% CI: 0.71 - 1.43]). The hourly growth in FFVIIa was 0.998 times that for placebo ([95% CI: 0.994 - 1.003]).
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Catheter Tract Hemorrhages and Intracerebral Hemorrhage Outcomes in the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Trial
Garton, A. L. A., Oh, S. E., Müller, A., Avadhani, R., Zhang, C., Merkler, A. E., Awad, I., Hanley, D., Kamel, H., Ziai, W. C., et al
Neurosurgery. 2023
Abstract
BACKGROUND AND OBJECTIVES Factors associated with external ventricular catheter tract hemorrhage (CTH) are well studied; whether CTH adversely influence outcomes after intracerebral hemorrhage (sICH), however, is poorly understood. We therefore sought to evaluate the association between CTH and sICH outcomes. METHODS We performed a post hoc analysis of the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage trial. The exposure was CTH and evaluated on serial computed tomography scans between admission and randomization (approximately 72 hours). The primary outcomes were a composite of death or major disability (modified Rankin Score >3) and mortality alone, both assessed at 6 months. Secondary outcomes were functional outcomes at 30 days, permanent cerebrospinal fluid (CSF) shunt placement, any infection, and ventriculitis. We performed logistic regression adjusted for demographics, comorbidities, sICH characteristics, and treatment assignment, for all analyses. RESULTS Of the 500 patients included, the mean age was 59 (SD, ±11) years and 222 (44%) were female. CTH occurred in 112 (22.4%) patients and was more common in minority patients, those on prior antiplatelet therapy, and patients who had more than 1 external ventricular drain placed. The end of treatment intraventricular hemorrhage volume was higher among patients with CTH (11.7 vs 7.9 mL, P = .01), but there were no differences in other sICH characteristics or the total duration of external ventricular drain. In multivariable regression models, CTH was not associated with death or major disability (odds ratio, 0.7; 95% CI: 0.4-1.2) or death alone (odds ratio, 0.8; 95% CI, 0.5-1.4). There were no relationships between CTH and secondary outcomes including 30-day functional outcomes, permanent CSF shunt placement, any infection, or ventriculitis. CONCLUSION Among patients with sICH and large intraventricular hemorrhage, CTH was not associated with poor sICH outcomes, permanent CSF shunt placement, or infections. A more detailed cognitive evaluation is needed to inform about the role of CTH in sICH prognosis.
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Intraventricular Lavage vs External Ventricular Drainage for Intraventricular Hemorrhage: A Randomized Clinical Trial
Haldrup, M., Rasmussen, M., Mohamad, N., Dyrskog, S., Thorup, L., Mikic, N., Wismann, J., Grønhøj, M., Poulsen, F. R., Nazari, M., et al
JAMA network open. 2023;6(10):e2335247
Abstract
IMPORTANCE Intraventricular lavage has been proposed as a minimally invasive method to evacuate intraventricular hemorrhage. There is little evidence to support its use. OBJECTIVE To evaluate the safety and potential efficacy of intraventricular lavage treatment of intraventricular hemorrhage. DESIGN, SETTING, AND PARTICIPANTS This single-blinded, controlled, investigator-initiated 1:1 randomized clinical trial was conducted at Aarhus University Hospital and Odense University Hospital in Denmark from January 13, 2022, to November 24, 2022. Follow-up duration was 90 days. The trial was set to include 58 patients with intraventricular hemorrhage. Prespecified interim analysis was performed for the first 20 participants. Data were analyzed from February to April 2023. INTERVENTIONS Participants were randomized to receive either intraventricular lavage or standard drainage. MAIN OUTCOMES AND MEASURES The main outcome was risk of catheter occlusions. Additional safety outcomes were catheter-related infections and procedure time, length of stay at the intensive care unit, duration of treatment, and 30-day mortality. The main outcome of the prespecified interim analysis was risk of severe adverse events. Efficacy outcomes were hematoma clearance, functional outcome, overall survival, and shunt dependency. RESULTS A total of 21 participants (median [IQR] age, 67 [59-82] years; 14 [66%] male) were enrolled, with 11 participants randomized to intraventricular lavage and 10 participants randomized to standard drainage; 20 participants (95%) had secondary intraventricular hemorrhage. The median (IQR) Graeb score was 9 (5-11), and the median (IQR) Glasgow Coma Scale score was 6.5 (4-8). The study was terminated early due to a significantly increased risk of severe adverse events associated with intraventricular lavage at interim analysis (risk difference for control vs intervention, 0.43; 95% CI, 0.06-0.81; P = .04; incidence rate ratio for control vs intervention, 6.0; 95% CI, 1.38-26.1; P = .01). The rate of catheter occlusion was higher for intraventricular lavage compared with drainage (6 of 16 patients [38%] vs 2 of 13 patients [7%]; hazard ratio, 4.4 [95% CI, 0.6-31.2]; P = .14), which met the prespecified α = .20 level. Median (IQR) procedure time for catheter placement was 53.5 (33-75) minutes for intraventricular lavage vs 12 (4-20) minutes for control (P < .001). CONCLUSIONS AND RELEVANCE This randomized clinical trial of intraventricular lavage vs standard drainage found that intraventricular lavage was encumbered with a significantly increased number of severe adverse events. Caution is recommended when using the device to ensure patient safety. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT05204849.
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Tranexamic Acid in Non-Traumatic Intracerebral Haemorrhage (TANICH II): Introducing the Potential Role of 3 g Tranexamic Acid in Haematoma Reduction
Arumugam, A., Tan, S. E., Tan, S. L., Tan, J. E., Hussin, F. H., Zenian, M. S., Idris, Z., Abdullah, J. M.
The Malaysian journal of medical sciences : MJMS. 2023;30(3):93-102
Abstract
BACKGROUND Intracerebral haemorrhage (ICH) can be devastating, particularly if haematoma expansion occurs. The efficacy of tranexamic acid (TXA), an anti-fibrinolytic agent, in reducing haematoma expansion is now being studied worldwide. However, the optimal dosage of TXA has yet to be determined. This study was designed to further establish the potential of different doses of TXA. METHODS A double-blinded, randomised, placebo-controlled study was carried out among adults with non-traumatic ICH. Eligible study subjects were randomly assigned to receive placebo, 2-g TXA treatment or 3-g TXA treatment. Haematoma volumes before and after intervention were measured using the planimetric method. RESULTS A total of 60 subjects with 20 subjects in each treatment group were recruited for this study. Among the 60 subjects, the majority were male (n = 36, 60%), had known cases of hypertension (n = 43, 71.7%) and presented with full Glasgow coma scale (GCS) (n = 41, 68.3%). The results showed that there was no statistically significant difference (P = 0.315) in the mean changes of haematoma volume when compared with three study groups using ANCOVA, although the 3-g TXA group was the only group that showed haematoma volume reduction (mean reduction of 0.2 cm(3)) instead of expansion as in placebo (mean expansion 1.8 cm(3)) and 2-g TXA (mean expansion 0.3 cm(3)) groups. Good recovery was observed in all study groups, with only three subjects being moderately disabled. No adverse effects were reported in any of the study groups. CONCLUSION To the best of our knowledge, this is the first clinical study using 3 g of TXA in the management of non-traumatic ICH. From our study, 3 g of TXA may potentially be helpful in reducing haematoma volume. Nonetheless, a larger-scale randomised controlled trial should be carried out to further establish the role of 3 g of TXA in non-traumatic ICH.
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Exploring Hematoma Expansion Shift with Recombinant Factor VIIa: A Pooled Analysis of Four Randomized Controlled Trials
Yogendrakumar, V., Mayer, S. A., Steiner, T., Broderick, J. P., Dowlatshahi, D.
Stroke. 2023
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Abstract
Background: Hematoma expansion shift (HES) analysis can be used to assess the biological effect of a hemostatic therapy for intracerebral hemorrhage. In this study we applied HES analysis to individual patient data from four randomized controlled trials evaluating recombinant Factor VIIa (rFVIIa) 80 μg/kg to placebo. Methods: We generated polychotomous strata of HES using absolute growth thresholds (≤0mL/<6mL/≥6mL) and quintiles of percent volume change. The relationship between treatment and HES was assessed using proportional odds models. Differences in subgroups based on baseline volume (≥ or <20 mL) and time from symptom onset to treatment (≤ or >2 hours) were explored with testing for interactions. Results: The primary analysis included 721 patients. At 24 hours, 36% (134/369) of rFVIIa treated patients exhibited no hematoma expansion as compared to 25% of placebo (88/352) treated patients. Significant expansion (≥6 mL) was reduced by 10% in those treated with rFVIIa (acOR:0.57, 95% CI:0.43-0.75). An examination of percent change similarly showed a shift across the spectrum of expansion (acOR: 0.61, 95% CI: 0.47-0.80). In both groups, mild to moderate expansion was observed in 38 to 47% of patients, depending on the threshold used. Differences in absolute HES between the rFVIIa and placebo groups were more pronounced in patients with baseline hemorrhage volumes ≥20 mL (acOR 0.48, 95% CI: 0.30-0.76 versus <20 mL: acOR:0.67, 95% CI:0.47-0.95, p(interaction)= 0.02). No treatment interaction in patients treated within 2 or after 2 hours from onset was observed (acOR:0.42, 95% CI:0.19-0.91 versus >2 hours: acOR:0.59, 95% CI:0.44-0.79, p(interaction)=0.30). Conclusions: The association between rFVIIa and hematoma growth arrest is most pronounced in patients with larger baseline volumes but is evident across the full spectrum of treated patients.
