Thrombolytics+in+Acute+Stroke

=__Alteplase__=

//**NINDS-tPA 1 and 2, 1995**//: Tissue Plasminogen Activator for Acute Ischemic Stroke. NEJM 1995;333 1581-7.
 * treatment: t-PA 0.9 mg/kg (max 90 mg) 10% given as bolus followed by 90% as constant infusion over 60 minutes
 * control: placebo
 * population: ischemic stroke with clearly defined time of onset, deficit measurable on NIHSS, and baseline CT showing no evidence of ICH
 * method: RCT, intention-to-treat
 * follow-up: part 1- 24h, part 2- 3 months
 * primary end-point: part 1- complete resolution of neurologic deficit or NIHSS recovery of >=4 at 24h after stroke; part 2- minimal or no deficits 3 months after treatment
 * outcome: part 1: no significant difference at 24 hours, although benefit was observed for the t-PA group at 3 mo for all 4 outcome measures. In part 2, global odds ratio for a favorable odds rati with t-PA vs placebo was 1.7 (CI 1.2 to 2.7), t-PA group was at least 30% more likely to have minimal or no disability at 3 months on the assessment scales. Increased ICH with t-PA. No significant difference in mortality.

//**ECASS, 1995 and ECASS2, 1998**//: investigated a time window of up to 6 hours but failed to show the efficacy of thrombolytic treatment, as definited by each trial
 * ECASS: Hacke et al, “Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA 1995; 274-1017-25.
 * ECASII: Hacke et al, “Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASSII). Lancet 1998; 352:1245-51.

//**ATLANTIS, 1999**//: Clark et al, “Recombinant Tissue-Type Plasminogen Activator (Alteplase) for Ischemic Stroke 3 to 5 Hours After Symptom Onset: The ATLANTIS Study: A Randomized Controlled Trial.” JAMA 1999: 2019-26.
 * RCT, double-blind
 * N=613
 * Inclusion criteria: ages 18-79
 * Exclusion criteria: CT showing ICH or signs of cerebral ischemia in >1/3 of MCA territory
 * Treatment: 0.9 mg/kg tPA
 * Control: Placebo
 * Primary outcome: NIHSS =<1
 * Secondary outcomes: Excellent recovery on functional outcome measures (Barthel, Rankin, Glasgow) at days 30 and 90
 * Results: Primary outcome showed no significant difference (34% in tPA group, 32% in placebo group), no difference in secondary outcomes. More symptomatic ICH in tPA group (7.0% in tPA group, 1.1% in placebo group, P<0.001). 90-day mortality was 11.0% in tPA group and 6.9% in placebo group (P=0.09).

//**Pooled Analysis, 2004:**// Hacke et al. “Association of outome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials.” Lancet 2004; 363:768-74.
 * Combined analysis of data from 6 randomized trials
 * N=2775
 * Clear association of efficacy and the interval between onset of symptoms and administration of the thrombolytic agent
 * Favorable outcome observed even if treatment was given between 3 and 4.5 hours, with an odds ratio of 1.4 for a favorable outcome with tPA as compared with placebo
 * Longer time window not associated with increase in symptomatic ICH or death
 * OR for global outcome 2.81 for 0-90 minutes, 1.55 for 91-180 minutes, and 1.40 for 181-270 minutes.

//**SITS-MOST, 2007**//: Wahlgren et al, “Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study.” Lancet 2007; 369:275-82.
 * tPA as safe and effective in routine clinical practice as it is in RCTs

//**ECASS3, 2008**//: Hacke et al, “Thrombolysis with Alteplace 3 to 4.5 Hours after Acute Ischemic Stroke.” NEJM 2008.
 * Inclusion criteria: acute ischemic stroke, age 18-80, 3-4.5 hours, stroke symptoms present for at least 30 minutes with no significant improvement before treatment
 * Exclusion criteria: ICH, severe stroke as assessed clinically (NIHSS score >25) or on imaging as definied as a stroke involving more than one third of the MCA territory.
 * primary outcome: disability at 90 days
 * secondary outcome: composite of 4 neurologic and disability scores
 * n= 821
 * median time for administration of tPA: 3:59
 * results: favorable outcome with tPA (52.4%) greater than with placebo (45.2%), P=0.04
 * Any ICH: 27.0% with tPA, 17.6% with placebo, P=0.001
 * Symptomatic ICH: 2.4% with tPA, 0.2% with placebo, P=0.008
 * Mortality did not differ dignificantly between groups.
 * Conclusions: tPA 3-4.5 significantly improved outcomes with AIS (absolute benefit 7.2%, NNT 14), with increased symptomatic ICH in the tPA group (absolute harm 2.2%), and no difference in mortality between the groups.
 * Notes: Exluded severe stroke. ECASSII and ATLANTIS had 3-4.5 hour cohorts which were much smaller and therefore not powered to detect effect size of 7-10%. Funded by Boehringer Ingelheim

=__**Tenecteplase**__=

//**Tenecteplase vs. Alteplase**//: "A Ranomized Trial of Tenecteplase versus Alteplase for Acute Ischemic Stroke," Parsons et al, NEJM 2012; 366:1099-107. [|PUBMED]
 * Phase 2B trial
 * 75 patients, 25 received alteplase 0.9mg/kg, 25 received tenecteplase 0.1mg/kg, 25 received 0.25mg/kg
 * Eligibility criteria: perfusion lesions at least 20% greater than infarct core on CT and associated vessel occlusion on CTA
 * The two tenecteplase groups had greater reperfusion and clinical improvement at 24 hours than the alteplase group. No significant difference in ICH. The 0.25mg/kg tenecteplase dose was superior to the 0.1mg/kg tenecteplase dose and the alteplase dose for all efficacy outcomes, including absense of serious disability at 90 days.

[|UMHS tPA Packet]