57 research outputs found
Catabolism of C1 inhibitor influences the response to replacement therapy in hereditary angioedema
No full textExposure-Response Model of Subcutaneous C1-Inhibitor Concentrate to Estimate the Risk of Attacks in Patients With Hereditary Angioedema
No full textSubcutaneous C1-inhibitor (HAEGARDA, CSL Behring), is a US Food and Drug Administration (FDA)-approved, highly concentrated formulation of a plasma-derived C1-esterase inhibitor (C1-INH), which, in the phase III Clinical Studies for Optimal Management in Preventing Angioedema with Low-Volume Subcutaneous C1-inhibitor Replacement Therapy (COMPACT) trial, reduced the incidence of hereditary angioedema (HAE) attacks when given prophylactically. Data from the COMPACT trial were used to develop a repeated time-to-event model to characterize the timing and frequency of HAE attacks as a function of C1-INH activity, and then develop an exposure-response model to assess the relationship between C1-INH functional activity levels (C1-INH(f)) and the risk of an attack. The C1-INH(f) values of 33.1%, 40.3%, and 63.1% were predicted to correspond with 50%, 70%, and 90% reductions in the HAE attack risk, respectively, relative to no therapy. Based on trough C1-INH(f) values for the 40 IU/kg (40.2%) and 60 IU/kg (48.0%) C1-INH (SC) doses, the model predicted that 50% and 67% of the population, respectively, would see at least a 70% decrease in the risk of an attack
Treatment effect of switching from intravenous to subcutaneous C1-inhibitor for prevention of hereditary angioedema Attacks : COMPACT subgroup findings
No full textThrombolysis is associated with consistent functional improvement across baseline stroke severity: a comparison of outcomes in patients from the Virtual International Stroke Trials Archive (VISTA)
No full text<p><b>Background and Purpose:</b> Baseline stroke severity predicts outcomes among thrombolysed patients. The baseline National Institutes of Health Stroke Scale (NIHSS) thresholds are sometimes used to select patients for thrombolysis, clinical trial enrollment, or both. Using data lodged with Virtual International Stroke Trials Archive, we compared adjusted outcomes between thrombolysed and nonthrombolysed patients enrolled in neuroprotection trials (1998-2007) to assess the influence of various levels of baseline NIHSS.</p>
<p><b>Method:</b> We assessed the association of treatment with outcome, measured across the modified Rankin scale score distribution, in patients categorized by baseline NIHSS in increments of 4. We used an age and baseline NIHSS adjusted Cochran-Mantel-Haenszel test followed by proportional odds logistic regression analysis. We report the Cochran-Mantel-Haenszel P values and estimated odds ratios (OR) for improved modified Rankin scale score distribution with treatment for patients within each baseline NIHSS category.</p>
<p><b>Results:</b> Data were available for 5817 patients (1585 thrombolysed and 4232 nonthrombolysed). Baseline severity was greater among thrombolysed than nonthrombolysed (median baseline NIHSS, 14 vs 13; P<0.05). An association of treatment with outcome was seen independently and was of similar magnitude within each of the baseline NIHSS categories 5 to 8 (P=0.04; OR, 1.25; 95% confidence interval [CI], 1.0-1.6; N=278/934 thrombolysed/nonthrombolysed), 9 to 12 (P=0.01; OR, 1.3; 95% CI, 1.1-1.6; N=404/942), 13 to 16 (P<0.05; OR, 1.6; 95% CI, 1.3-2.1; N=342/814), 17 to 20 (P<0.05; OR, 1.7; 95% CI, 1.3-2.1; N=311/736), and 21 to 24 (P<0.05; OR, 1.6; 95% CI, 1.1-2.1; N=178/466). No association was observed within baseline NIHSS categories 1 to 4 (P=0.8; OR, 1.1; 95% CI, 0.3-4.4; N=8/161) or >= 25 (P=0.08; OR, 1.1; 95% CI, 0.7-1.9; N=64/179).</p>
<p><b>Conclusions:</b> In this nonrandomized comparison, outcomes after thrombolysis were significantly better than in untreated comparators across baseline NIHSS 5 to 24. The significant association was lost only at extremes of baseline NIHSS when sample sizes were small and confidence limits were wide.</p>
Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials: Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST)
No full text<p><b>Background and Purpose:</b> The Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST) unadjusted results demonstrated that intravenous alteplase is well tolerated and that the effects were comparable with those seen in randomized, controlled trials (RCTs) when used in routine clinical practice within 3 hours of ischemic stroke onset. We aimed to identify outcome predictors and adjust the outcomes of the SITS-MOST to the baseline characteristics of RCTs.</p>
<p><b>Methods:</b> The study population was SITS-MOST (n=6483) and pooled RCTs (n=464) patients treated with intravenous alteplase within 3 hours of stroke onset. Multivariable, backward stepwise regression analyses (until P≤0.10) were performed to identify the outcome predictors for SITS-MOST. Variables appearing either in the final multivariable model or differing (P<0.10) between SITS-MOST and RCTs were included in the prediction model for the adjustment of outcomes. Main outcome measures were symptomatic intracerebral hemorrhage, defined as National Institutes of Health Stroke Scale deterioration ≥1 within 7 days with any hemorrhage (RCT definition), mortality, and independency as defined by modified Rankin Score of 0 to 2 at 3 months.</p>
<p><b>Results:</b> The adjusted proportion of symptomatic intracerebral hemorrhage for SITS-MOST was 8.5% (95% CI, 7.9 to 9.0) versus 8.6% (6.3 to 11.6) for pooled RCTs; mortality was 15.5% (14.7 to 16.2) versus 17.3% (14.1 to 21.1); and independency was 50.4% (49.6 to 51.2) versus 50.1% (44.5 to 54.7), respectively. In the multivariable analysis, older age, high blood glucose, high National Institutes of Health Stroke Scale score, and current infarction on imaging scans were related to poor outcome in all parameters. Systolic blood pressure, atrial fibrillation, and weight were additional predictors of symptomatic intracerebral hemorrhage. Current smokers had a lower rate of symptomatic intracerebral hemorrhage. Disability before current stroke (modified Rankin Score 2 to 5), diastolic blood pressure, antiplatelet other than aspirin, congestive heart failure, patients treated in new centers, and male sex were related to high mortality at 3 months.</p>
<p><b>Conclusions:</b> The adjusted outcomes from SITS-MOST were almost identical to those in relevant RCTs and reinforce the conclusion drawn previously in the unadjusted analysis. We identified several important outcome predictors to better identify patients suitable for thrombolysis.</p>
Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke
No full textBackground: Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke, but its efficacy and safety when administered more than 3 hours after the onset of symptoms have not been established. We tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke.
Methods: After exclusion of patients with a brain hemorrhage or major infarction, as detected on a computed tomographic scan, we randomly assigned patients with acute ischemic stroke in a 1:1 double-blind fashion to receive treatment with intravenous alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, which has a range of 0 to 6, with 0 indicating no symptoms at all and 6 indicating death) or an unfavorable outcome (a score of 2 to 6 on the modified Rankin scale). The secondary end point was a global outcome analysis of four neurologic and disability scores combined. Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events.
Results: We enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes. More patients had a favorable outcome with alteplase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P=0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P<0.05). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial hemorrhage, 27.0% vs. 17.6%; P=0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differ significantly between the alteplase and placebo groups (7.7% and 8.4%, respectively; P=0.68). There was no significant difference in the rate of other serious adverse events.
Conclusions: As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage
Safety of intravenous thrombolysis for acute ischemic stroke in patients receiving antiplatelet therapy at stroke onset
No full text<p><b>Background and Purpose:</b> Antiplatelets (APs) may increase the risk of symptomatic intracerebral hemorrhage (ICH) following intravenous thrombolysis after ischemic stroke.</p>
<p><b>Methods:</b> We assessed the safety of thrombolysis under APs in 11 865 patients compliant with the European license criteria and recorded between 2002 and 2007 in the Safe Implementation of Treatments in Stroke (SITS) International Stroke Thrombolysis Register (SITS-ISTR). Outcome measures of univariable and multivariable analyses included symptomatic ICH (SICH) per SITS Monitoring Study (SITS-MOST [deterioration in National Institutes of Health Stroke Scale >= 4 plus ICH type 2 within 24 hours]), per European Cooperative Acute Stroke Study II (ECASS II [deterioration in National Institutes of Health Stroke Scale >= 4 plus any ICH]), functional outcome at 3 months and mortality.</p>
<p><b>Results:</b> A total of 3782 (31.9%) patients had received 1 or 2 AP drugs at baseline: 3016 (25.4%) acetylsalicylic acid (ASA), 243 (2.0%) clopidogrel, 175 (1.5%) ASA and dipyridamole, 151 (1.3%) ASA and clopidogrel, and 197 (1.7%) others. Patients receiving APs were 5 years older and had more risk factors than AP nave patients. Incidences of SICH per SITS-MOST (ECASS II respectively) were as follows: 1.1% (4.1%) AP naive, 2.5% (6.2%) any AP, 2.5% (5.9%) ASA, 1.7% (4.2%) clopidogrel, 2.3% (5.9%) ASA and dipyridamole, and 4.1% (13.4%) ASA and clopidogrel. In multivariable analyses, the combination of ASA and clopidogrel was associated with increased risk for SICH per ECASS II (odds ratio, 2.11; 95% CI, 1.29 to 3.45; P = 0.003). However, we found no significant increase in the risk for mortality or poor functional outcome, irrespective of the AP subgroup or SICH definition.</p>
<p><b>Conclusion:</b> The absolute excess of SICH of 1.4% (2.1%) in the pooled AP group is small compared with the benefit of thrombolysis seen in randomized trials. Although caution is warranted in patients receiving the combination of ASA and clopidogrel, AP treatment should not be considered a contraindication to thrombolysis.</p>
Relationship of blood pressure, antihypertensive therapy, and outcome in ischemic stroke treated with intravenous thrombolysis: retrospective analysis from Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR)
No full text<p><b>Background and Purpose:</b> The optimal management of blood pressure (BP) in acute stroke remains unclear. For ischemic stroke treated with intravenous thrombolysis, current guidelines suggest pharmacological intervention if systolic BP exceeds 180 mm Hg. We determined retrospectively the association of BP and antihypertensive therapy with clinical outcomes after stroke thrombolysis.</p>
<p><b>Methods:</b> The SITS thrombolysis register prospectively recorded 11 080 treatments from 2002 to 2006. BP values were recorded at baseline, 2 hours, and 24 hours after thrombolysis. Outcomes were symptomatic (National Institutes of Health Stroke Scale score deterioration ≥4) intracerebral hemorrhage Type 2, mortality, and independence at (modified Rankin Score 0 to 2) 3 months. Patients were categorized by history of hypertension and antihypertensive therapy within 7 days after thrombolysis: Group 1, hypertensive treated with antihypertensives (n=5612); Group 2, hypertensive withholding antihypertensives (n=1573); Group 3, without history of hypertension treated with antihypertensives (n=995); and Group 4, without history of hypertension not treated with antihypertensives (n=2632). For 268 (2.4%) patients, these data were missing. Average systolic BP 2 to 24 hours after thrombolysis was categorized by 10-mm Hg intervals with 100 to 140 used as a reference.</p>
<p><b>Results:</b> In multivariable analysis, high systolic BP 2 to 24 hours after thrombolysis as a continuous variable was associated with worse outcome (P<0.001) and as a categorical variable had a linear association with symptomatic hemorrhage and a U-shaped association with mortality and independence with systolic BP 141 to 150 mm Hg associated with most favorable outcomes. OR (95% CI) from multivariable analysis showed no difference in symptomatic hemorrhage (1.09 [0.83 to 1.51]; P=0.58) and independence (1.03 [0.93 to 1.10]; P=0.80) but lower mortality (0.82 [0.73 to 0.92]; P=0.0007) for Group 1 compared with Group 4. Group 2 had a higher symptomatic hemorrhage (1.86 [1.34 to 2.68]; P=0.0004) and mortality (1.62 [1.41 to 1.85]; P<0.0001) and lower independence (0.89 [0.80 to 0.99]; P=0.04) compared with Group 4. Group 3 had similar results as Group 1.</p>
<p><b>Conclusions:</b> There is a strong association of high systolic BP after thrombolysis with poor outcome. Withholding antihypertensive therapy up to 7 days in patients with a history of hypertension was associated with worse outcome, whereas initiation of antihypertensive therapy in newly recognized moderate hypertension was associated with a favorable outcome.</p>
P159 Attacks avoided and cost offsets associated with subcutaneous C1-inhibitor (human) long-term prophylaxis of hereditary angioedema
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