Recombinant Tissue Plasminogen Activator for Acute Ischemic Stroke

Saurav Chatterjee, MD

Review

Wardlaw JM, Murray V, Berge E, et al. Recombinant tissue plasminogen activator for acuteischaemic stroke: an updated systematic review and meta-analysis. Lancet. Published onlineMay 23, 2012. doi:10.1016/S0140-6736(12)60738-7.

In their systematic review and metaanalysis, Wardlaw et al report on the clinical outcomes of administration of recombinant tissue-type plasminogen activator (rt-PA) as treatment for acute-onset ischemic stroke (CVA).1 The authors performed an updated systematic evaluation and synthesis of available data on the topic, especially in view of favorable results with the recently published Third International Stroke Trial (IST-3), with a resultant analysis with greater inferential power than the individual randomized controlled trials (RCTs) available. The study tries to delineate areas of lacunae in care of acute stroke that have not been addressed in current guidelines.

Licensing authorities in the US and Europe have approved use of intravenous rt-PA within 3 hours of onset of symptoms of acute stroke based largely on the National Institute of Neurological Disorders and Stroke (NINDS) trial.2 Subsequent trials,3 as well as meta-analyses,4 have identified benefits with administration of rt-PA even at 6 hours after symptom onset. The authors attempted to evaluate the evidence for using intravenous rt-PA for a wide range of patients, including those older than 80 years, treated between 3 hours and 6 hours after symptom onset, and with comorbid disorders such as previous stroke, diabetes, or hypertension.

Study Design

The methodology was sound, following standard protocols specified by the Cochrane group for meta-analytic evaluation of randomized data. The authors searched different databases and registries, as well as published literature, using multiple overlapping search methods up to March 2012 for relevant trials of rt-PA. The authors even translated non-English-language publications and obtained additional information from principal investigators to validate their study. They estimated summary odds ratios (ORs) and 95% confidence intervals (CIs) in the primary analysis for prespecified outcomes within 7 days and at the final follow-up in individual trials of all patients treated up to 6 hours after stroke. After identifying and screening 400 articles on the topic, 12 studies were selected by the authors for the quantitative analysis. The total rt-PA dose was about 0.6 mg/kg to 1.1 mg/kg. In up to 12 trials (7012 patients), rt-PA given within 6 hours of stroke significantly increased the odds of being alive and independent (modified Rankin Scale [mRS], 0-2) at final follow-up (1611/3483 [46.3%] versus 1434/3404 [42.1%]; OR, 1.17; 95% CI, 1.06-1.29; P = 0.001), absolute increase of 42 (19-66) per 1000 people treated, and favorable outcome (mRS, 0-1), absolute increase of 55 (95% CI, 33-77) per 1000. The benefit of rt-PA was greatest in patients treated within 3 hours (mRS, 0-2); (365/896 [40.7%] versus 280/883 [31.7%]; OR, 1.53; 95% CI, 1.26-1.86; P<0.0001), absolute benefit of 90 (46-135) per 1000 people treated, and mRS 0-1 (283/896 [31.6%] versus 202/883 [22.9%]; OR, 1.61; 95% CI, 1.30-1.90; P <0.0001), absolute benefit 87 (46-128) per 1000 treated. Numbers of deaths within 7 days were increased (250/2807 [8.9%] versus 174/2728 [6.4%]; OR, 1.44; 95% CI, 1.18-1.76; P = 0.0003), but by final follow-up the excess was no longer significant (679/3548 [19.1%] versus 640/3464 [18.5%]; OR, 1.06; 95% CI, 0.94-1.20; P = 0.33). However, this analysis was accompanied by significant heterogeneity of findings as indicated by the chi-square test. Symptomatic intracranial hemorrhage (272/3548 [7.7%] versus 63/3463 [1.8%]; OR, 3.72; 95% CI, 2.98-4.64; P <0.0001) accounted for most of the early excess deaths. Patientsolder than 80 years achieved similar benefit to those ages 80 years or younger, particularly when treated early (Table). Rates of cerebral edema were also not elevated with use of rt-PA. However, all-cause mortality, and especially mortality of intracranial hemorrhage, was significantly higher in the first 7 days (29 more deaths per 1000 treated patients) after treatment with t-PA; when outcomes were evaluated at the end of follow-up for the individual trials, the difference disappeared in that there was a statistically nonsignificant increase of 7 more deaths per 1000 patients treated. The authors suggest that the evidence indicates intravenous rt-PA increased the proportion of patients who were alive with favorable outcome and alive and independent at final follow-up. They also recommended treatment with rt-PA as early as possible after acute ischemic stroke, although some patients might benefit up to 6 hours after stroke.

References

1. Wardlaw JM, Murray V, Berge E, et al. Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis [published online ahead of print May 23, 2012]. Lancet.

2. The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischaemic stroke. N Engl J Med. 1995;333:1581-1587.

3. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274:1017-1025.

4. Wardlaw JM, Sandercock PAG, Berge E. Thrombolytic therapy with recombinant tissue plasminogen activator for acute ischemic stroke. Where do we go from here? a cumulative metaanalysis. Stroke. 2003;34:1437-1442.

5. Wardlaw JM, del Zoppo G, Yamaguchi T, Berge E. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev. 2003;CD000213.

6. Cheung PK, Arnold JM, McLarty TD. Splenic hemorrhage: a complication of tissue plasminogen activator treatment. Can J Cardiol. 1990;6:183-185.

7. Poppe AY, Majumdar SR, Jeerakathil T, Ghali W, Buchan AM, Hill MD. Canadian Alteplase for Stroke Effectiveness Study Investigators. Admission hyperglycemia predicts a worse outcome in stroke patients treated with intravenous thrombolysis. Diabetes Care. 2009;32:617-622.

8. Alvarez-Sabín J, Molina CA, Montaner J, et al. Effects of admission hyperglycemia on stroke outcome in reperfused tissue plasminogen activator-- treated patients. Stroke. 2003;34:1235-1241.

9. Young FB, Weir CJ, Lees KR; GAIN International Trial Steering Committee and Investigators. Comparison of the National Institutes of Health Stroke Scale with disability outcome measures in acute stroke trials. Stroke. 2005;36:2187-2192.

COMMENTARY

Benefit of Early rt-PA- for Acute Ischemic Stroke

Wardlaw et al present us with a well-conducted meta-analysis with reiteration of benefit of early rt-PA therapy for acute ischemic stroke. Their conclusions concur with a similar prior meta-analysis by many of the same authors, arriving at virtually the same conclusion.5 However, a few interesting issues merit deliberation:

1. The favorable outcomes with rt-PA were largely driven by improvements in functional outcomes, while actual mortality was significantly higher in the first 7 days, and numerically (but nonsignificantly) higher with rt-PA administration at the end of follow-up. This indicates a very real risk of death from intracerebral hemorrhage in the first 7

days after rt-PA therapy, with the enticing prospect of better neurologic outcomes if one survives the peri-therapeutic time window. Also the benefits of rt-PA beyond 3 hours of symptom onset were not convincing, and were statistically inferior to rt-PA within the first 3 hours.

2. The authors did not report on bleeding from sites other than intracerebral hemorrhage, though that is a significant risk as well with rt-PA use.6

3. The authors did not report on outcomes in patients with comorbidities from the meta-analytic data, as originally mentioned in their hypothesis and intended analysis. 7,8

4. The study provides strong evidence for extending use of thrombolytic therapy in patients older than 80 years of age, provided they can consent after appropriately evaluating the risks and benefits of such a course of therapy.

5. In spite of rigorous statistical adjustments, the different scales used for assessing neurological outcomes in individual studies may have influenced the combined outcome.9 In summary, this systematic review suggests that intravenous rt-PA increased the proportion of patients who were alive with favorable outcome and alive and

independent at final follow-up. The analysis strengthens previous evidence to treat patients as early as possible after acute ischemic stroke, although some patients, even the elderly over 80 years, might benefit up to 6 hours after stroke. The key message from contemporary trials and the meta-analysis is that many eligible patients from subgroups excluded by the current drug labeling may benefit from rt-PA. Every stroke patient should, therefore, be evaluated as a candidate for thrombolysis. Future research is needed to delineate specific characteristics of patients who may derive the maximum benefit, while exposing themselves to minimal risk.

About the Author

Saurav Chatterjee, MD, is Clinical and Research Fellow in Preventive Cardiology and Outcomes Research at Brown University and Providence VAMC in Providence, RI. He graduated from Calcutta National Medical College with honors and was a Resident in Cardiology at Mercy Hospital, Kolkata, India, as well as trial coordinator of the CRESCENDO trial in Kolkata, India. He has recently finished his residency in Internal Medicine at Maimonides Medical Center in Brooklyn, NY. Dr Chatterjee is the recipient of the 2012 Young Investigator Award for Health Outcomes and Population Genetics at the Annual Scientific Sessions of the American College of Cardiology 2012 in Chicago, and also the 2011 American Association of Cardiologists of Indian Origin (AACIO) Young Investigator Award for Interventional Cardiology and Electrophysiology.