Thrombolysis in very elderly people: controlled comparison of SITS International Stroke Thrombolysis Registry and Virtual International Stroke Trials Archive
BMJ 2010; 341 doi: https://doi.org/10.1136/bmj.c6046 (Published 24 November 2010) Cite this as: BMJ 2010;341:c6046All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
Mishra et al's controlled comparison from the SITS-VISTA regarding
thrombolysis in the very elderly may represent a positive step forward in
the management of acute ischaemic strokes.1 Stroke is currently the second
leading cause of death in the Western World 2, commonly arising secondary
to ischaemia from thrombo-embolic events.3 With a rapidly aging population
and the increasing incidence of metabolic syndrome in the UK, it will be
no surprise if it soon takes the top stop as the major cause of mortality
in the country. Hence, there is a drive for addressing risk factors and to
develop measures to reduce morbidity should an acute event occur.
Besides spending 2 months of my Foundation Year 1 on a Stroke firm, I
feel somewhat closely connected to the disease as my 81 year old
grandmother, who helped raise me, recently suffered from one. She was
admitted to hospital for decompensation of her heart failure and suffered
a massive right anterior cerebral and middle cerebral artery territory
infarct while having her dinner. Despite her initial normal CT brain scan
and few risk factors of long-standing well controlled diabetes and
hypertension, the decision was made not to thrombolyse on the basis that
the risks outweighed the benefits. Her level of consciousness gradually
deteriorated and repeat CT scans demonstrated a large infarct with a
profound midline shift. She eventually succumbed to a chest infection and
passed away 3 weeks after her original stroke.
The study provides a stepping stone for clinicians to carry out
randomized controlled trials prior to implementation in clinical practice
with information solely based from two registries. This can be further
supported by the lack of significant differences in rates of intracerebral
haemorrhages in the mentioned age groups.1 Even so; I fear the recognition
and transfer of elderly patients to thrombolysis centres, usually located
in tertiary hospitals or urban areas, within the 4.5 hour limit may pose a
challenge with many of them living by themselves or in rural areas.
References
1. Nishant K Mishra, Niaz Ahmed, Grethe Andersen, Jose A Egido,
Perttu J Lindsberg, Peter A Ringleb, Nils G Wahlgren, Kennedy R
Lees(2010).Thrombolysis in very elderly people: controlled comparison of
SITS International Stroke Thrombolysis Registry and Virtual International
Stroke Trials Archive.BMJ 341:doi:10.1136/bmj.c6046
2. Murray CJ, Lopez AD (1997).Mortality by cause for eight regions of
the world: Global Burden of Disease Study. Lancet 349 (9061): 1269-76.
doi:10.1016/S0140-6736(96)07493-4. PMID 9142060.
3. Ian Baker (2007) The Incidence, Aetiology and Management of Stroke
http://www.dh.gov.uk/en/Aboutus/Researchanddevelopment/AtoZ/Cardiovascul...
Competing interests: No competing interests
Dear Ms. Godlee
Permit me to introduce myself. My name is Derek Whitehead and,
although I am not medically qualified, I have had a major involvement with
stroke.
My late wife, Barbara, had her first stroke in 1999, with a further
four strokes during the next four years, leaving her totally paralysed,
unable to speak and doubly incontinent - and I looked after her at home,
in that condition, for the next five years.
She was used as a case study in the NAO stroke report of 2005 and I
was invited to be a lay member of the team which wrote the National Stroke
Strategy. I then played a part in the implementation of the new stroke
treatments in Greater Manchester - and for this work I was awarded the
MBE. The full implementation of these procedures in Greater Manchester was
celebrated in May 2010 by a conference which was dedicated to the memory
of Barbara - and see the BBC television report within this link
http://www.gmccsn.nhs.uk/index.php/galleryprof?gid=7
When the initial trials of Alteplase were conducted in 1995, it made
perfect sense to exclude the over eighties, on the grounds that it might
confuse the outcome - but that was 15 years ago.
More recently I have put pressure on Professor Roger Boyle to extend
the Alteplase licence to include the over eighties by analysing the
available IST-3 data - as has been done by Professor Lees et al - and I
hope that the work of Professor Lees and his team will make this
procedural change happen in the immediate future.
Most worthwhile things in life involve an element of risk and reward.
In the case of the use of Alteplase on medically suitable stroke patients,
who are over eighty, I believe that the potential reward vastly exceeds
the potential risk.
Yours sincerely
Derek Whitehead MBE MSc BSc
Competing interests: No competing interests
The paper by Mishra and colleagues suggests that age should not be a
barrier to stroke thrombolysis but we advise caution in using
observational data to change clinical guidelines before robust evidence
from the ongoing randomised controlled trials (RCTs) are available.1
Firstly, SITS is a voluntary registry, it is known not to include all
patients that receive rt-PA and in particular, patients who suffer adverse
events (like haemorrhage and death) may be omitted. VISTA is a trials
registry so includes all patients, once they are entered into the trials,
without selective loss. In a non-randomised comparison such as that of
Mishra et al, a simple selection bias could produce the apparent
difference between outcomes in SITS and VISTA that the authors have
attributed to rt-PA.
Secondly, there is no mention of the time of treatment, but SITS is a
registry of rt-PA use within licence and therefore largely refers to
patients treated within 3, at most 4.5 hours after stroke. The
neuroprotective trials in VISTA largely had time windows of six hours.
Mishra et al do not even mention whether their data samples were taken
from patients treated within the same time windows, or whether they
matched SITS cases and VISTA controls for time to treatment. All they
apparently matched on was age and stroke severity. The fact that they may
have taken no account of time at all is suggested by the statement "we had
data on age and the stroke scale for our entire sample, whereas data on
other factors of potential interest were incomplete". One would reasonably
expect that time to treatment would be of "potential interest". Without
the simple step of matching for time, their analysis is invalid.
These two serious flaws could explain one of several misleading
analyses e.g. as revealed by their results on the effect of alteplase on
death by 3 months. The systematic review of all RCTs demonstrated that
thrombolysis non-significantly increased deaths, at best a neutral effect
if given within three hours, yet in the Mishra analysis there was a 3.5%
absolute decrease in deaths at three months in the alteplase treated
patients.2 This entire effect can be attributed to the potential margin of
error of an observational study compared to an RCT. Much more telling is
the increase in symptomatic intracranial haemorrhage (SICH) rate in those
treated with rt-PA aged >80 years old (11%) versus <80 (8.3%), OR
1.4, 95% CI 1.2 to1.6; P<0.001, the key adverse outcome after rt-PA,
which they unfortunately could not compare with the VISTA controls as the
latter did not have routine follow-up brain imaging. Assuming that the
VISTA controls had a similar SICH rate to control groups of RCTs (ie
<1%)2, then we can reasonably estimate that the SICH rate in the over
80s given rt-PA in SITS is increased eleven-fold, or an OR >5, somewhat
higher than the OR of 3 seen in RCTs including mainly patients <80
years old. Sadly, SITS does not even contribute to knowledge of risk
factors for SICH in the over 80s because it does not collect relevant
data.
Hence, it is most unwise to use their data to suggest that the
treatment of people greater than 80 years is "safe". In the large recent
observational study on the use of rt-PA 'off-label' from Helsinki,
Meretoja and colleagues described that in patients aged over 80 years, rt-
PA was associated with a poorer outcome than among those treated according
to the European licence.3
We are encouraged that Mishra's observational study confirms our
belief that thrombolysis is a very promising treatment for those aged 80
years old. However, until the results of the Third International Stroke
Trial are reported (expected in the first half of 2012), we would
recommend physicians consider randomising appropriate patients into the
ongoing trials (IST-3, TESPI) to ensure we have robust evidence of
effectiveness for the 21st century. Appropriate use of thrombolysis for
stroke has been hampered by the limitations of the randomised trial
evidence for over a decade. We urge readers to increase the size of the
current RCT database on the effects in people over 80 from the present few
(startlingly, only 67 patients). These data will be needed to inform
treatment decisions for the several million people aged over 80 years old
who are expected to present to hospital with acute stroke over the next
few decades.
References
1) Mishra NK, Ahmed N, Andersen G, Egido JA, Lindsberg PJ, Ringleb
PA, Wahlgren NG, Lees KR for the VISTA and SITS collaborators.
Thrombolysis in very elderly people: controlled comparison of SITS
International Stroke Thrombolysis Registry and Virtual International
Stroke Trials Archive. BMJ 2010; 341:c6046 doi:10.1136/bmj.c6046
2) Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for
acute ischemic stroke. Stroke 2010 published online Apr 15, 2010 DOI:
10.1161/STROKEAHA.109.575530
3) Meretoja A, Putaala J, Tatlisumak T, Atula S, Artto V, Curtze S,
Happola O, Lindsberg PJ, Mustanoja S, Piironen K, Pitkaniemi 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.
Competing interests: The authors have spent more than a decade running the Third International Stroke Trial (www.ist3.com) in order to provide reliable data to expand the current licensed indications for stroke thrombolysis.RIL has received support to attend national stroke meetings, and received honoraria from Boehringer Ingelheim for services as scientific committee member.PAGS has received modest fees for serving as a member of the Independent Data Monitoring Committee of the RELY trial funded by Boehringer Ingelheim.Joanna Wardlaw has no financial conflicts of interest.
Thrombolysis in very elderly people
Reading with interest the article, it would be valuable to indicate
some considerations :
-The very old in-patients in neurologic departments and medicine
departments : it is observed a higher percentage in cardiovascular risk
factors ( HTA and DM )difference between such services.
( Castilla Guerra 2005 )
-The series by Molto considering carotid diseaase in the very elderly
( 2009 ), found less complex plaques and non-rough surfaces, although
not significant, in this age range.
-The series by Kimura ( 2008 ) considering haemorrhagic
transformation of ischemic brain after thrombolysis ( silent hemorrhagia )
were not significant in r correlation for age ( > 75 ) in silent
in P, S , L types of silent haemorrhages ).
Competing interests: No competing interests