Response to Letter by Longstreth and Tirschwell
We thank Drs Longstreth and Tirschwell1 for their comments on our article on off-label use of alteplase in stroke patients.2 Naturally, we did not reference their article on the National Institute of Neurological Disorders and Stroke (NINDS) trial patients older than 80 years because their article was published only after our final version was accepted.3 Unfortunately, their article adds little light to the question of thrombolysis in the octogenarians, because they do not report baseline characteristics when imbalances could easily explain differences with such small numbers of patients (19 placebo vs 25 alteplase). They also use an unclear definition for a symptomatic intracerebral hemorrhage, different from the several existing definitions, which makes their report difficult to compare with other data.
In our series of 1000 consecutive patients treated with intravenous alteplase in routine practice, 16% were older than 80 years. We found a trend toward excess symptomatic intracerebral hemorrhage with advanced age, which became nonsignificant in multivariate analysis, after potential confounders had been taken into account; the difference was mostly explained by baseline elevated glucose and early infarct signs. Our material even included 12 patients older than 90 years, of whom only 1 had a symptomatic intracerebral hemorrhage according to the European cooperative acute stroke study criteria, and 4 had a good outcome at 3 months (modified Rankin Scale score, 0–2), and similar results in the oldest patients have been reported elsewhere.4
Irrespective of symptomatic intracerebral hemorrhage, older age and more severe baseline symptoms are the most important predictors of outcome in any stroke patient, and thus it is only natural that older patients fare worse than younger ones after thrombolysis. This also was the case in our cohort treated with ultra-early thrombolysis in which lower blood glucose level, younger age, lower baseline National Institutes of Health Stroke Scale, and onset-to-needle time <70 minutes were associated with better outcome.5 Although advanced age reduces the likelihood of good outcome, this does not mean that alteplase would cease to benefit stroke patients after a certain age.
We think that with carefully streamlined services, thrombolytic therapy can benefit a fair portion of ischemic stroke patients, including octogenarians. In the year 2009, we treated 265 patients, 22% of our ischemic stroke patients, with alteplase, and over the past year we have achieved a median onset-to-needle time of 115 minutes and door-to-needle time of 20 minutes. We will continue to treat octogenarians with alteplase when otherwise indicated, just as do many other seasoned stroke services in Europe and elsewhere. Streamlined systems and well-trained teamwork may, in part, explain our better results compared with the patients in the NINDS trial. The pivotal trial opened the gates for thrombolysis in stroke 15 years ago, but many things have improved in stroke care since.
The Third International Stroke Trial aims to randomize ≈1000 patients (www.dcn.ed.ac.uk/ist3) and the Italian TESPI trial 600 patients (www.strokecenter.org/trials) older than 80 years to intravenous alteplase vs placebo. These trials will increase our knowledge of alteplase safety and efficacy, specifically in the older patients, and the first results are awaited in spring of 2012. While waiting for these, we consider it unethical to withhold treatment based on patient’s age only.
A.M. received honoraria from Boehringer Ingelheim (modest). M.K. received honoraria from Boehringer Ingelheim, PAION AG, Forest Research Laboratories, and Lundbeck AS for participating in Steering Committee meetings of all ECASS and Desmoteplase in Acute Ischemic Stroke Trial (DIAS) trials (modest), and is a consultant for and on the Advisory Boards of Boehringer Ingelheim, PAION AG, Forest Research Laboratories, and Lundbeck AS (modest).
Longstreth WT Jr, Tirschwell DL. Intravenous thrombolysis in patients older than age 80 years. Stroke. 2010; 41: e580.
Meretoja A, Putaala J, Tatlisumak T, Atula S, Artto V, Curtze S, Häppölä O, Lindsberg PJ, Mustanoja S, Piironen K, Pitkäniemi J, Rantanen K, Sairanen T, Salonen O, Silvennoinen H, Soinne L, Strbian D, Tiainen M, Kaste M. Off-label thrombolysis is not associated with poor outcome in patients with stroke. Stroke. 2010; 41: 1450–1458.
Mateen FJ, Buchan AM, Hill MD; on behalf of the CASES Investigators. Outcomes of thrombolysis for acute ischemic stroke in octogenarians versus nonagenarians. Stroke. 2010; 41: 1833–1835.
Strbian D, Soinne L, Sairanen T, Häppölä O, Lindsberg PJ, Tatlisumak T, Kaste M; for the Helsinki Stroke Thrombolysis Registry Group. Ultraearly thrombolysis in acute ischemic stroke is associated with better outcome and lower mortality. Stroke. 2010; 41: 712–716.