Influence of time metrics on the treatment effect of intravenous alteplase prior to endovascular treatment in MR CLEAN-NO IV.

BACKGROUND: We assessed whether the treatment effect of intravenous alteplase (IVT) prior to endovascular treatment (EVT) on functional outcome is modified by time metrics. METHODS: We used data from all patients included in MR CLEAN-NO IV, a randomized trial of IVT followed by EVT versus EVT alone in patients who presented directly to EVT-capable hospitals. The primary outcome was the modified Rankin Scale score at 90 days. We used ordinal regression with a multiplicative interaction term to assess if the effect of IVT is modified by onset-to-randomization (OTR), onset-to-IV-needle (OTN), door-to-groin (DTG) or needle-to-groin (NTG) times. Secondary outcomes included successful reperfusion (extended Thrombolysis In Cerebral Infarction Scale 2b-3) and symptomatic intracranial hemorrhage (sICH). RESULTS: In 539 included patients (266 allocated to IVT+EVT and 273 to EVT alone), median workflow times were OTR: 93 (IQR 71-145) min; OTN: 98 (IQR 75-156) min; DTG: 64 (IQR 51-78) min; and NTG: 28 (IQR 20-41) min. There was a significant association between worse outcomes and longer time intervals for all metrics except NTG. We found no interaction between any of the time metrics and IVT for the effect on functional outcome (p values for interaction: OTR=0.40, OTN=0.39, DTG=0.61, NTG=0.56). We also did not observe any significant interaction for successful reperfusion or sICH. CONCLUSION: In MR CLEAN-NO IV, the effect of IVT prior to EVT was not modified by OTR, OTN, DTG or NTG times. Our results do not support the use of these metrics to guide IVT treatment decisions prior to EVT in comprehensive stroke centres. TRIAL REGISTRATION NUMBER: ISRCTN80619088.

Hemorrhage rates in patients with acute ischemic stroke treated with intravenous alteplase and thrombectomy versus thrombectomy alone.

BACKGROUND: Intravenous alteplase treatment (IVT) for acute ischemic stroke carries a risk of intracranial hemorrhage (ICH). However, reperfusion of an occluded vessel itself may contribute to the risk of ICH. We determined whether IVT and reperfusion are associated with ICH or its volume in the Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN)-NO IV trial. METHODS: The MR CLEAN-NO IV trial randomized patients with acute ischemic stroke due to large vessel occlusion to receive either IVT followed by endovascular treatment (EVT) or EVT alone. ICH was classified according to the Heidelberg bleeding classification on follow-up MRI or CT approximately 8 hours-7 days after stroke. Hemorrhage volume was measured with ITK-snap. Successful reperfusion was defined as extended Thrombolysis In Cerebral Infarction (eTICI) score of 2b-3. Multinomial and binary adjusted logistic regression were used to determine the association of IVT and reperfusion with ICH subtypes. RESULTS: Of 539 included patients, 173 (32%) developed ICH and 30 suffered from symptomatic ICH (sICH) (6%). Of the patients with ICH, 102 had hemorrhagic infarction, 47 had parenchymal hematoma, 44 had SAH, and six had other ICH. Reperfusion was associated with a decreased risk of SAH, and IVT was not associated with SAH (eTICI 2b-3: adjusted OR 0.45, 95% CI 0.21 to 0.97; EVT without IVT: OR 1.6, 95% CI 0.91 to 2.8). Reperfusion status and IVT were not associated with overall ICH, hemorrhage volume, and sICH (sICH: EVT without IVT, OR 0.96, 95% CI 0.41 to 2.25; eTICI 2b-3, OR 0.49, 95% CI 0.23 to 1.05). CONCLUSION: Neither IVT administration before EVT nor successful reperfusion after EVT were associated with ICH, hemorrhage volume, and sICH. SAH occurred more often in patients for whom successful reperfusion was not achieved.

Type of intracranial hemorrhage after endovascular stroke treatment: association with functional outcome.

BACKGROUND: Intracranial hemorrhage (ICH) is a frequent complication after endovascular stroke treatment. OBJECTIVE: To assess the association of the occurrence and type of ICH after endovascular treatment (EVT) with functional outcome. METHODS: We analyzed data from the MR CLEAN-NO IV and MR CLEAN-MED trials. Both trials included adult patients with ischemic stroke with a large vessel occlusion in the anterior circulation, who were eligible for EVT. ICH was classified (1) as asymptomatic or symptomatic (concomitant neurological deterioration of ≥4 points on the NIHSS, or ≥2 points on 1 NIHSS item), and (2) according to the Heidelberg Bleeding Classification. We used multivariable ordinal logistic regression analyses to assess the association of the occurrence and type of ICH with the modified Rankin Scale score at 90 days. RESULTS: Of 1017 included patients, 331 (33%) had an asymptomatic ICH, and 90 (9%) had a symptomatic ICH. Compared with no ICH, both asymptomatic (adjusted common OR (acOR)=0.76; 95% CI 0.58 to 0.98) and symptomatic (acOR=0.07; 95% CI 0.04 to 0.14) ICH were associated with worse functional outcome. In particular, isolated parenchymal hematoma type 2 (acOR=0.37; 95% CI 0.14 to 0.95), combined parenchymal hematoma with hemorrhage outside infarcted brain tissue (acOR=0.17; 95% CI 0.10 to 0.30), and combined hemorrhages outside infarcted brain tissue (acOR=0.14; 95% CI 0.03 to 0.74) were associated with worse functional outcome than no ICH.Strength of the association of ICH with functional outcome depends on the type of ICH. Although the association is stronger for symptomatic ICH, asymptomatic ICH after EVT is also associated with worse functional outcome.

Association Between Beta-Blocker or Statin Drug Use and the Risk of Hemorrhage From Cerebral Cavernous Malformations.

BACKGROUND: We aimed to determine the association between beta-blocker or statin drug use and the future risk of symptomatic intracranial hemorrhage or persistent/progressive focal neurological deficit from cerebral cavernous malformations (CCM). METHODS: The population-based Scottish Audit of Intracranial Vascular Malformations prospectively identified adults resident in Scotland first diagnosed with CCM during 1999 to 2003 or 2006 to 2010. We compared the association between beta-blocker or statin drug use after first presentation and the occurrence of new intracranial hemorrhage or persistent/progressive focal neurological deficit due to CCM for up to 15 years of prospective follow-up. We confirmed proportional hazards and used survival analysis with multivariable adjustment for age, intracranial hemorrhage at CCM presentation, and brain stem CCM location. RESULTS: Sixty-three (21%) of 300 adults used beta-blockers (27/63 [43%] used propranolol), and 73 (24%) used statin drugs over 3634 person-years of follow-up. At baseline, the only statistically significant imbalances in prespecified potential confounders were age by statin use and intracranial hemorrhage at presentation by beta-blocker use. Beta-blocker use was associated with a lower risk of new intracranial hemorrhage or persistent/progressive focal neurological deficit (adjusted hazard ratio, 0.09 [95% CI, 0.01-0.66]; P=0.018). Statin use was associated with a nonsignificant lower risk of intracranial hemorrhage or persistent/progressive focal neurological deficit (adjusted hazard ratio, 0.37 [95% CI, 0.01-1.07]; P=0.067). CONCLUSIONS: Beta-blocker, but not statin, use was associated with a lower risk of intracranial hemorrhage or persistent/progressive focal neurological deficit in patients with CCM.

Stereotactic radiosurgery for cerebral cavernous malformations: A systematic review.

OBJECTIVE: The efficacy of stereotactic radiosurgery (SRS) for the treatment of cerebral cavernous malformations (CCMs) is uncertain, so we set out to quantify clinical outcomes after SRS for CCM and compare them to microsurgical excision or conservative management. METHODS: We searched Ovid Medline and Ovid EMBASE from inception until June 1, 2018, for peer-reviewed publications describing clinical outcomes after SRS for ≥10 people with CCM in cohorts with or without a comparison group treated with neurosurgical excision or conservative management. Two reviewers independently extracted data from the included studies to quantify cohort characteristics and the incidence of the primary outcome (death attributable to CCM or its treatment) and secondary outcomes (incident nonfatal symptomatic intracerebral hemorrhage [ICH] and incident nonhemorrhagic persistent focal neurologic deficit [FND]). We assessed whether comparative studies showed a dramatic association (meaning the conventionally calculated probability comparing 2 differently managed patient groups from the same population was <0.01 with a rate ratio greater than 10). RESULTS: We included 30 cohort studies involving a total of 1,576 patients undergoing SRS for CCM. Four nonrandomized studies compared SRS to other treatment strategies, but did not demonstrate dramatic associations. During a median follow-up of 48 (interquartile range 35-62) months after SRS, the annual incidences (95% confidence interval) of outcomes were death 0.18% (0.10-0.31), ICH 2.40% (2.05-2.80), FND 0.71% (0.53-0.96), and the composite of death, ICH, or FND 3.63% (3.17-4.16). Outcomes did not differ by CCM location or type of SRS. CONCLUSION: After SRS for CCM, the annual incidences of death, ICH, and FND are <5% and seem comparable to outcomes without SRS. A randomized trial of SRS for CCM is needed.

Long-term antithrombotic therapy and risk of intracranial haemorrhage from cerebral cavernous malformations: a population-based cohort study, systematic review, and meta-analysis.

BACKGROUND: Antithrombotic (anticoagulant or antiplatelet) therapy is withheld from some patients with cerebral cavernous malformations, because of uncertainty around the safety of these drugs in such patients. We aimed to establish whether antithrombotic therapy is associated with an increased risk of intracranial haemorrhage in adults with cerebral cavernous malformations. METHODS: In this population-based, cohort study, we used data from the Scottish Audit of Intracranial Vascular Malformations, which prospectively identified individuals aged 16 years and older living in Scotland who were first diagnosed with a cerebral cavernous malformation during 1999-2003 or 2006-10. We compared the association between use of antithrombotic therapy after first presentation and the occurrence of intracranial haemorrhage or persistent or progressive focal neurological deficit due to the cerebral cavernous malformations during up to 15 years of prospective follow-up with multivariable Cox proportional hazards regression assessed in all individuals identified in the database. We also did a systematic review and meta-analysis, in which we searched Ovid MEDLINE and Embase from database inception to Feb 1, 2019, to identify comparative studies to calculate the intracranial haemorrhage incidence rate ratio according to antithrombotic therapy use. We then generated a pooled estimate using the inverse variance method and a random effects model. FINDINGS: We assessed 300 of 306 individuals with a cerebral cavernous malformation who were eligible for study. 61 used antithrombotic therapy (ten [16%] of 61 used anticoagulation) for a mean duration of 7·4 years (SD 5·4) during follow-up. Antithrombotic therapy use was associated with a lower risk of subsequent intracranial haemorrhage or focal neurological deficit (one [2%] of 61 vs 29 [12%] of 239, adjusted hazard ratio [HR] 0·12, 95% CI 0·02-0·88; p=0·037). In a meta-analysis of six cohort studies including 1342 patients, antithrombotic therapy use was associated with a lower risk of intracranial haemorrhage (eight [3%] of 253 vs 152 [14%] of 1089; incidence rate ratio 0·25, 95% CI 0·13-0·51; p<0·0001; I2=0%). INTERPRETATION: Antithrombotic therapy use is associated with a lower risk of intracranial haemorrhage or focal neurological deficit from cerebral cavernous malformations than avoidance of antithrombotic therapy. These findings provide reassurance about safety for clinical practice and require further investigation in a randomised controlled trial. FUNDING: UK Medical Research Council, Chief Scientist Office of the Scottish Government, The Stroke Association, Cavernoma Alliance UK, and the Remmert Adriaan Laan Foundation.

Radiosurgical, neurosurgical, or no intervention for cerebral cavernous malformations: A decision analysis.

INTRODUCTION: We aimed to evaluate the preferred treatment strategy for patients with symptomatic cerebral cavernous malformations (CCM). METHODS: In a decision model, we compared neurosurgical, radiosurgical, and conservative management. A literature review yielded the risks and outcomes of interventions, intracerebral hemorrhage (ICH), and seizures. Patients with CCM rated their quality of life to determine utilities. We estimated the expected number of quality-adjusted life years (QALYs) and the ICH recurrence risk over five years, according to mode of presentation and CCM location (brainstem vs. other). We performed analyses with a time horizon of five years. RESULTS: Using the best available data, the expected number of QALYs for brainstem CCM presenting with ICH or focal neurological deficit was 2.84 (95% confidence interval [CI]: 2.54-3.08) for conservative, 3.01 (95% CI: 2.86-3.16) for neurosurgical, and 3.03 (95% CI: 2.88-3.18) for radiosurgical intervention; those for non-brainstem CCM presenting with ICH or focal neurological deficit were 3.08 (95% CI: 2.85-3.31) for conservative, 3.21 (95% CI: 3.01-3.36) for neurosurgical, and 3.19 (95% CI: 2.98-3.37) for radiosurgical intervention. For CCM presenting with epilepsy, QALYs were 3.09 (95% CI: 3.03-3.16) for conservative, 3.33 (95% CI: 3.31-3.34) for neurosurgical, and 3.27 (95% CI: 3.24-3.30) for radiosurgical intervention. DISCUSSION AND CONCLUSION: For the initial five years after presentation, our study provides Class III evidence that for CCM presenting with ICH or focal neurological deficit conservative management is the first option, and for CCM presenting with epilepsy CCM intervention should be considered. More comparative studies with long-term follow-up are needed.