Sanaz Sakiani, MD Endocrinology Fellow Journal Club

 IV Alteplase was granted marketing authorization in Europe in 2002  But patients with prior stroke (PS) and concomittant diabetes (DM) were excluded from approval.  “the therapeutic benefit is reduced in patients that had a PS or in whom an uncontrolled DM is known, thus the benefit/risk ratio is considered less favorable, but still positive in these patients”  EMEA-mandated third European Cooperative Acute Stroke Study (ECASS-III)  Was required to exclude patients with PS and concomitant DM from its protocol as a result of this review

 In 1995, the NINDS study reported that patients with acute ischemic stroke (AIS) who received alteplase (IVtPA) w/in 3h after onset of symptoms were 30% more likely to have min or no disability at 90 days compared to those who received placebo.  Two European trials, ECASS and ECASS II, investigated a time window of up to 6hrs but failed to show efficacy of thrombolytic txt  A subsequent re-analysis of the NINDS study and a pooled analysis of data from 6 randomized trials with 2275 pts showed a clear association between treatment efficacy and the interval between the onset of symptoms and IVtPA treatment  In the pooled analysis, a favorable outcome was observed even if treatment was given between 3 and 4.5 hours  This analysis also suggested that a longer time window was not associated with higher rates of sICH or death.

 In 2002, the European Medicines Evaluation Agency (EMEA) approved the use of tPA for treatment of stroke within 3h.  This was contingent on 2 conditions:  Completion of a registry of pts treated with tPA within 3 h (Safe Implementation of Thrombolysis in Stroke-Monitoring Study, SITS-MOST), and  Completion of prosp, randomized, placebo-controlled trial of tPA use within hrs—ECASS-III  In 2008, ECASS-III was completed showing that there was benefit to treating with tPA within the 3 to 4.5 hour range.  Exclusion criteria:  Pts older than 80 yo  NIHSS>25  Anyone taking oral anticoagulants  Those with previous stroke and diabetes  Other traditional tPA inclusion and exclusion criteria

 In routine clinical practice, many such patients (PS, DM, both) are treated, but others may not be due to confusion over the evidence  This trial looked to examine the treatment effect of IV alteplase in pts with DM, PS, or both.  Clarify the validity of the rationale behind the restriction  For EMEA’s restriction to be valid, it should be found that the benefit/risk ratio would be lowered independently in each subgroup, or at least diminished within the combined group due to an interaction of DM with PS

SITS-ISTR Safe Implementation of Thrombolysisin Stroke-International Stroke Thrombolysis Register Dec 2002 – Nov ,136 23,336 Had completed 90day follow-up or died within 90days 2 patients excluded because inaccurate age information VISTA Virtual International Stroke Trials Archive ,665 6,317 Had AIS and were not given thrombolytic 205 Excluded because of missing Rankin scores at 90days 29,500 pts for analysis 272 patients were missing NIH Stroke Scale score (NIHSS) data n = 29, 228

 Outcomes compared between patients who received thrombolysis and those who didn’t among patients with DM, PS, or both  For each contrast, they compared the overall distribution of all 7 categories of day 90 modified Rankin scores of the 2 groups  0 - No symptoms.  1 - No sig disability. Able to do all usual activities, despite some sympt.  2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.  3 - Mod disability. Requires some help, but able to walk unassisted.  4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.  5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.  6 - Dead.

 More patients in the DM group have HTN, history of PS, Afib, CHF, and used antithrombotic agents before stroke  Patients who received treatment had had a more severe stroke at baseline compared to the untreated patients  More patients in the PS group had HTN, DM, Afib, CHF, and use of antithrombotic agents before stroke

 Nonrandomized  Patients with PS who were offered thrombolysis may have had higher premorbid mRS than patients who had no PS  Patients with premorbid mRS >1 were excluded from the VISTA trials from which our comparators are derived  This potential bias would be expected to lead to an underestimation of any benefit from alteplase in that subgroup of patients.

 The analysis shows improved outcomes in patients with DM or PS that is comparable to other patient groups.  This finding contrasts with EMEA’s justification for restricting the use of IV alteplase  Did not confirm a significant benefit in the small subgroup of patients who had concomitant DM and PS, but the CI’s were wide and there was no interaction between these 2 risk factors with the treatment effect of alteplase.  The authors find no justification to exclude these patients