doi: 10.1161/01.STR.0000210167.37729.eb
(Stroke. 2006;37:942.)
© 2006 American Heart Association, Inc.
Letters to the Editor |
Referral Bias May Underestimate Number of Very Elderly Patients Eligible for rtPA
Division of Clinical Neurosciences, University of Glasgow, Institute of Neurological Sciences, Southern General Hospital, Glasgow, Scotland, UK
To the Editor:
We read with interest the article by Berrouschot and colleagues on the outcome and complications of intravenous (IV) thrombolysis with recombinant tissue plasminogen activator (rtPA) in stroke patients aged 
80 years.1 Although randomization of patients in this age group into the ongoing IST-3 trial will expand the evidence base for treatment in patients aged >80 years, both within 3 hours and 3 to 6 hours of onset, most active thrombolysis centers receive referrals for older patients who currently fall outside licensing restrictions in Europe on the basis of age alone. Treatment is felt by many to be justified on the basis of observational data and the small amount of randomized controlled trial data.2 There is sparse information on numbers and source of referral for the elderly in the thrombolysis literature.
We undertook a prospective log of all referrals to our unit for thrombolysis over a 12-month period (July 2004 through June 2005). Of 188 referrals, 43/188 (23%) were patients aged 80 years. Excluding 7 patients aged 80, who would be eligible for thrombolysis on the basis of current licensing, 36/188 (19%) would have been ineligible for treatment only on the basis of age. Our unit has no age limit on treatment within 3 hours provided all other criteria are satisfied, the patient or their representative is in agreement with a treatment decision, and with the proviso that all treated patients are registered with Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR). Eight patients aged >80 years received IV rtPA (median age 84, IQR: 83, 87). Of 312 patients with confirmed acute ischemic stroke admitted to the unit over the 12-month study period, IV rtPA was given to 8/67 (12%) aged >80 years, compared with 41/245 (17%) of patients aged 
80 years. Those over 80 years of age were not significantly less likely to be treated (Odds ratio 0.67, 95% CIs 0.23 to 1.52, P=0.45 [Fisher exact test]).
Our stroke unit provides both a local comprehensive stroke service to around 350 000 population, and is a regional neurosciences center covering 2.5 million people over a wide geographical area. For patients aged >80, the majority of referrals came from primary care and already hospitalized patients (30.5% each). Local and regional emergency departments accounted for 28% and 11% of referrals, respectively. This differed from patients aged 80 years, where the referral sources were emergency departments (72%), primary care (23%) and inpatients (5%) (
2 test; P<0.001). Of patients referred but having contraindications to treatment based on the European product license, 22/33 (67%) had only age as a contraindication for referrals from primary care or inpatients, whereas age was the only factor in 13/49 (26.5%) referred from emergency departments (P<0.001).
Based on our experience, a high proportion of patients may be excluded from IV rtPA on grounds of age alone. Referral bias is present, but treatment rates did not differ significantly from the under 80s in our service for those assessed. The bias against referral by emergency departments that we saw may reflect a harsher judgment of functional status in the very elderly, but does not appear to reflect knowledge or application of current license criteria. Discrepancies in baseline functional status between patients aged >80 and those 80 may explain higher mortality and reduced favorable outcome in the elderly population. Failure to control for baseline differences may underestimate the benefit of thrombolysis with the recognition that hemorrhage rates do not differ significantly.
The outcomes reported by Berrouschot et al are consistent with the Canadian Alteplase for Stroke Effectiveness Study (CASES) series,3 and reflect our own experience. Using prestroke modified Rankin Scale to adjust for baseline discrepancies, the CASES series found a 16% relative increase in patients achieving an excellent outcome.3,4 Continued registration of patients older than 80 in SITS-ISTR will allow wider analysis.
References
1. Berrouschot J, Rother J, Glahn J, Kucinski T, Fiehler J, Thomalla G. Outcome and severe hemorrhagic complications of intravenous thrombolysis with tissue plasminogen activator in very old (80 years) stroke patients. Stroke. 2005; 36: 2421–2425.
2. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995; 333: 1581–1588.
3. Hill MD, Buchan AM. Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study. CMAJ. 2005; 172: 1307–1312.
4. van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988; 19: 604–607.
Klinik und Poliklinik für Neurologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
Neurologische Klinik, Klinikum Minden, Universität Hannover, Minden, Germany
Neurologische Klinik, Kreiskrankenhaus Altenburg, Altenburg, Germany
Response:
We thank Drs McCormick and Muir for their comments on our article and the report of their practice with acute stroke treatment in very old patients, which is very much in line with our own proceeding. Their results further strengthen the main conclusion of our study: the outcome of intravenous thrombolysis may be worse in very old patients, but this is not related to thrombolysis, but to worse stroke outcome in elderly in general, and to a more severe initial neurological deficit in the very old patients. Because the risk of severe hemorrhagic complications is not increased in very old patients, and even in the very old a notable number of patients reaches a favorable outcome after thrombolysis (26% in our study), thrombolytic therapy seems justified in this increasing stroke population.
In this context, 2 recently published studies are of interest. The analysis of stroke patients treated with intravenous tPA from a Swiss databank showed a higher mortality in patients 80 years (32% versus 12%), whereas the percentage of patients with a favorable 3-month outcome was comparable between very old and younger patients (29% versus 37%).1 Moreover, logistic regression did not identify age as an independent predictor of outcome in this sample. In another patient series from Texas, the results were similar with a higher mortality, but comparable rates of improvement and symptomatic intracerebral hemorrhage in patients aged 80 years and over.2
In their letter Drs McCormick and Muir addressed the problem of a potential bias leading to lower referral rates of very old patients to thrombolysis centers. Such a bias might further contribute to the lower tPA treatment rates in patients aged 80 and over. In the European BIOMED study of stroke care 30% of all strokes occurred in the group aged 80 and over.3 In contrast to this, in the group of tPA treated patients, the proportion of patients 80 years ranges somewhat lower, between 12% in the Swiss databank1 and 16% in our study.4 A higher incidence of contraindications against tPA, such as anticoagulation or severe comorbidity in older patients, may contribute to lower rates. However, neither in our study nor in the sample reported by McCormick and Muir, those aged 80 and older were less likely to be treated with tPA than younger patients.
To conclude, in a substantial number of patients, age is the only contraindication against thrombolysis with tPA. A growing number of studies reported on intravenous thrombolysis in old and very old patients, and none of these studies provides evidence to exclude patients from tPA treatment, only because they have trespassed an arbitrary age limit. Hopefully, results from ongoing randomized controlled trials will provide more evidence. Until then, carefully selected very old stroke patients should not be deferred from intravenous tPA, which is the only effective acute ischemic stroke therapy.
References
1. Engelter ST, Reichhart M, Sekoranja L, Georgiadis D, Baumann A, Weder B, Muller F, Luthy R, Arnold M, Michel P, Mattle HP, Tettenborn B, Hungerbuhler HJ, Baumgartner RW, Sztajzel R, Bogousslavsky J, Lyrer PA. Thrombolysis in stroke patients aged 80 years and older: Swiss survey of IV thrombolysis. Neurology. 2005; 13; 65: 1795–1798.
2. Chen CI, Iguchi Y, Grotta JC, Garami Z, Uchino K, Shaltoni H, Alexandrov AV. Intravenous tPA for very old stroke patients. Eur Neurol. 2005; 54: 140–144.[CrossRef][Medline] [Order article via Infotrieve]
3. Di Carlo A, Lamassa M, Pracucci G, Basile AM, Trefoloni G, Vanni P, Wolfe CD, Tilling K, Ebrahim S, Inzitari D. Stroke in the very old: clinical presentation and determinants of 3-month functional outcome: a European perspective. European BIOMED Study of Stroke Care Group. Stroke. 1999; 30: 2313–2319.
4. Berrouschot J, Rother J, Glahn J, Kucinski T, Fiehler J, Thomalla G. Outcome and severe hemorrhagic complications of intravenous thrombolysis with tissue plasminogen activator in very old (80 years) stroke patients. Stroke. 2005; 36: 2421–2425.
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  S. T. Engelter, L. H. Bonati, and P. A. Lyrer Intravenous thrombolysis in stroke patients of >=80 versus <80 years of age--a systematic review across cohort studies. Age Ageing, November 1, 2006; 35(6): 572 - 580. [Abstract] [Full Text] [PDF]
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