Effect of Treatment of Elevated Blood Pressure on Neurological Deterioration in Patients with Acute Intracerebral Hemorrhage

Suri, M. Fareed K.; Suárez, José I.; Rodrigue, Tina; Zaidat, Osama O.; Vázquez, Gabriela; Wensel, A.; Selman, Warren R.

doi:10.1007/s12028-008-9106-7

Cited by 31 publications

(15 citation statements)

References 18 publications

(23 reference statements)

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“…These studies have shown that the benefit of DFO in ameliorating secondary neuronal injury after ICH is mediated via several diverse mechanisms and may be at least partly independent of its iron-chelating effects [5, 10–12]. Our findings that the MAP decreases by approximately 2 mmHg during DFO infusions indicates that DFO also exerts a mild BP-lowering effect, which may be of some potential benefit in ICH [27]. Therefore, DFO is a rational choice for further investigations as a potential therapeutic intervention to improve the outcome of patients with ICH.…”

Section: Discussionmentioning

confidence: 77%

Safety and Tolerability of Deferoxamine Mesylate in Patients With Acute Intracerebral Hemorrhage

Selim

Yeatts

Goldstein

et al. 2011

Stroke

131

100

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Background and Purpose Treatment with the iron chelator, deferoxamine mesylate (DFO), improves neurological recovery in animal models of Intracerebral hemorrhage (ICH). We aimed to evaluate the feasibility, safety, and tolerability of varying dose-tiers of DFO in patients with spontaneous ICH, and to determine the Maximum Tolerated Dose (MTD) to be adopted in future efficacy studies. Methods A multicenter, phase-I, dose-finding study using the Continual Reassessment Method. DFO was administered by an intravenous infusion for 3 consecutive days, starting within 18 hours of ICH onset. Subjects underwent repeated clinical assessments through 90 days, and CT neuroimaging pre- and post-drug administration. Results Twenty subjects were enrolled into 5 dose tiers, starting with 7 mg/kg/day and ending with 62 mg/kg/day as the MTD. Median age was 68 years (range: 50–90); 60% were men; and median GCS and NIHSS scores on admission were 15 (5–15) and 9 (0–39), respectively. ICH location was lobar in 40%, deep in 50%, and brainstem in 10%; intraventricular hemorrhage was present in 15%. DFO was discontinued due to adverse events in 2 subjects (10%). Six subjects (30%) experienced 12 serious adverse events (SAEs), none were drug-related. DFO infusions were associated with mild blood pressure lowering effects. Fifty percent of patients had mRS ≤2 and 39% had mRS 4–6 on day-90; 15% died. Conclusions Consecutive daily infusions of DFO after ICH are feasible, well-tolerated, and not associated with excessive SAEs or mortality. Our findings lay the groundwork for future studies to evaluate the efficacy of DFO in ICH.

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Section: Discussionmentioning

confidence: 77%

Safety and Tolerability of Deferoxamine Mesylate in Patients With Acute Intracerebral Hemorrhage

Selim

Yeatts

Goldstein

et al. 2011

Stroke

131

100

View full text Add to dashboard Cite

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“…To translate these findings into the clinical setting, we completed a Phase I dose-finding study to determine the maximum-tolerated dose of DFO in ICH patients [14]; DFO infusions up to 62 mg/kg/day were well tolerated with an acceptable safety profile. A Phase II clinical trial [high dose deferoxamine (Hi-Def) in ICH] is currently under way to assess the futility of DFO as a therapeutic intervention in ICH before embarking on a large Phase III trial.…”

Section: Introductionmentioning

confidence: 99%

High Dose Deferoxamine in Intracerebral Hemorrhage (Hi-Def) Trial: Rationale, Design, and Methods

et al. 2013

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Background Hemoglobin degradation products, in particular iron, have been implicated in secondary neuronal injury following intracerebral hemorrhage (ICH). The iron chelator Deferoxamine Mesylate (DFO) exerts diverse neuroprotective effects, reduces perihematoma edema (PHE) and neuronal damage, and improves functional recovery after experimental ICH. We hypothesize that treatment with DFO could minimize neuronal injury and improve outcome in ICH patients. As a prelude to test this hypothesis, we conducted a Phase I, open-label study to determine the tolerability, safety, and maximum tolerated dose (MTD) of DFO in patients with ICH. Intravenous infusions of DFO in doses up to 62 mg/kg/day (up to a maximum of 6000 mg/day) were well-tolerated and did not seem to increase serious adverse events (SAEs) or mortality. We have initiated a multi-center, double-blind, randomized, placebo-controlled, Phase II clinical trial (High Dose Deferoxamine [HI-DEF] in Intracerebral Hemorrhage) to determine if it is futile to move DFO forward to Phase III efficacy evaluation. Methods We will randomize 324 subjects with spontaneous ICH to either DFO at 62 mg/kg/day (up to a maximum daily dose of 6000 mg/day) or saline placebo, given by intravenous infusion for 5 consecutive days. Treatment will be initiated within 24 hours after ICH symptom onset. All subjects will be followed for 3 months and will receive standard of care therapy while participating in the study. At 3 months, the proportion of DFO-treated subjects with a good clinical outcome, assessed by modified Rankin Scale, will be compared to the placebo proportion in a futility analysis. Conclusions The Hi-Def trial is expected to advance our understanding of the pathopgysiology of secondary neuronal injury in ICH and will provide a crucial “Go/No Go” signal as to whether a Phase III trial to investigate the efficacy of DFO is warranted.

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“…5,10,12,13,15 For example, a prospective study of 105 patients with ICH showed that a rapid decline in mean BP within 24 hours was associated with higher inhospital mortality, 10 whereas another study involving 688 patients with ICH showed no association between early SBP reduction and death or disability at 3 weeks. 15 A prospective , and ∆SBP 2-7D , respectively.…”

Section: Discussionmentioning

confidence: 99%

“…study of 122 patients with ICH demonstrated lower rates of early neurological deterioration after ICH to be associated with larger SBP reductions, even with ≥64 mm Hg. 12 Such variability likely relates to differences in study design, patient selection, sample size, and measurement error, in particular of SBP levels according to time from ICH onset.…”

Section: Discussionmentioning

confidence: 99%

“…Some studies have implied adverse effects from reducing systolic BP (SBP), [8][9][10] whereas others have indicated clinical improvement with higher SBP reduction [11][12][13][14] or no benefits at all of such treatment in ICH. 15 An important meta-regression analysis of randomized controlled trials of altered BP in acute stroke showed a J-shaped relationship, with the best outcomes from modest SBP reduction (<10 mm Hg), but the number of patients included with ICH was limited.…”

mentioning

confidence: 99%

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Magnitude of Blood Pressure Reduction and Clinical Outcomes in Acute Intracerebral Hemorrhage

et al. 2015

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Abstract-Evidence supports early intensive blood pressure (BP) lowering in acute intracerebral hemorrhage, but uncertainty persists over whether potential benefits and harms vary according to the magnitude of BP reduction. We aimed to determine whether larger systolic BP (SBP) reductions were associated with better outcomes in participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). INTERACT2 was an international, open, blinded end point, randomized controlled trial of patients with spontaneous intracerebral hemorrhage (<6 hours) and elevated SBP (150-220 mm Hg) assigned to intensive (target SBP <140 mm Hg) or guideline-recommended (SBP <180 mm Hg) treatment. Associations of BP reduction (baseline minus average of achieved SBP) during 3 time periods post randomization (15-60 minutes, 1-24 hours, and 2-7 days) on poor outcome (death or major disability) at 90 days were analyzed in multivariable logistic regression models with odds ratios and 95% confidence intervals. Larger SBP reductions within the first hour after randomization were associated with lower risks of poor outcome: compared with minimal reduction (<10 mm Hg), odds ratios were 0.80 (95% confidence interval, 0.63-1.02) for moderate (10-20 mm Hg) and 0.65 (0.52-0.82) for large (≥20 mm Hg) reductions (P trend <0.01). Similar associations were also observed for SBP reductions during 1 to 24 hours (P<0.01) and 2 to 7 days (P 0.02). No heterogeneity in associations for patients above or below baseline SBP 180 mm Hg was reported (P>0.30). Optimal recovery from intracerebral hemorrhage was observed in hypertensive patients who achieved the greatest SBP reductions (≥20 mm Hg) in the first hour and maintained for 7 days. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00716079.

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Effect of Treatment of Elevated Blood Pressure on Neurological Deterioration in Patients with Acute Intracerebral Hemorrhage

Abstract: This study supports that reduction of blood pressure in patients with acute ICH is safe and suggests that aggressive reduction might reduce the risk of neurological deterioration in first 24 h of admission.

Cited by 31 publications

References 18 publications

Safety and Tolerability of Deferoxamine Mesylate in Patients With Acute Intracerebral Hemorrhage

Safety and Tolerability of Deferoxamine Mesylate in Patients With Acute Intracerebral Hemorrhage

High Dose Deferoxamine in Intracerebral Hemorrhage (Hi-Def) Trial: Rationale, Design, and Methods

Magnitude of Blood Pressure Reduction and Clinical Outcomes in Acute Intracerebral Hemorrhage

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