Intern Emerg Med DOI 10.1007/s11739-014-1097-0
LETTER TO THE EDITOR
Thrombolysis in the elderly: yes but with caution Simona Sacco • Silvia Ricci • Francesca Pistoia Antonio Carolei
•
Received: 1 June 2014 / Accepted: 9 June 2014 Ó SIMI 2014
Dear Editor We have followed with interest the debate referring to the implementation of the Italian guidelines on thrombolysis in ischemic stroke [1, 2] and would add some further cues. The relevance of looking for an effective and safe acute stroke treatment to elderly patients is beyond question. Stroke is very common in the elderly; in fact, about 35 % of all strokes occur in subjects over 80 years of age [3, 4], and with aging of the population, the number of elderly subjects having strokes will increase worldwide. However, elderly patients were excluded or underrepresented in the randomized-controlled trials of i.v. thrombolysis because an 80 year age limit was an exclusion criterion at that time, that was developed to limit the occurrence of complications, and to increase the chances of a better outcome associated with thrombolysis. Unfortunately, evidence of any benefit in this age group was unobtainable, and for this reason early guidelines recommended thrombolysis only in subjects aged less than 80 years. From that time onward, efforts have been made to overcome that age limit, so that several studies found benefits even in subjects aged 80 years or older [5]. This has led to the modification of the recommendations granting extension of the indications for i.v. thrombolysis to the oldest-old in several national guidelines, including the Italian ones [6]. In principle, we agree that older age should no longer represent a pre-defined exclusion criterion for thrombolysis, but we also suggest that future research and guidelines should move toward identification of robust criteria to S. Sacco (&) S. Ricci F. Pistoia A. Carolei Department of Applied Clinical Sciences and Biotechnology, Institute of Neurology, University of L’Aquila, via Vetoio, 67100 L’Aquila, Italy e-mail: [email protected]
allow a reliable selection of those elderly subjects who may have a true benefit from treatment in the absence of any significant risks. In almost all instances, elderly patients included in the available clinical studies on thrombolysis are those showing, on the basis of physicians’ evaluations, a high likelihood of benefits and a low risk of complications. Future studies should translate into clinical practice the mostly subjective criteria that were used by the clinicians to select subjects included into clinical trials. In addition, we want to underscore that in the IST-3 trial, patients aged [90 years represent a small subset of the overall elderly patients, and the efficacy and safety of the treatment in this specific age group is not reported [5]. Moreover, in the same trial, thrombolysis is associated with high 7-day mortality for intracerebral hemorrhage. In the elderly there is a higher incidence of cerebral small-vessel disease and cerebral microbleeds that may represent markers of increased risk of thrombolysis-related intracerebral hemorrhage. Furthermore, older patients have a relevant burden of medical comorbidities, and up to onethird of them have pre-stroke disability or dementia. The impact of thrombolysis in those circumstances is greatly controversial. Besides, we should keep in mind that elderly patients are those with higher rates of in-hospital complications that are predictors of death and disability, and that then chances of recovery can be hampered by reduced neuronal plasticity, baseline disability, and poorer social supports. Moreover, as thrombolysis is an expensive treatment, in the patients aged [90 years, the cost–benefit ratio is likely to be high, with consequent ethical implications. For all the above reported reasons, we need reliable criteria to select the appropriate candidates for i.v. thrombolysis. Key issues known to be predictive of outcome should help in guiding clinical judgment, leading to
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Intern Emerg Med
appropriate patient selection. Important factors to be considered are age (80 vs more than 90 years), stroke severity and subtype, pre-stroke disability, dementia, any relevant comorbidity as well as the personal wishes of the subject and family. Future studies should help to develop successful predictive scores, to select the elderly patients who have the greater likelihood to benefit from thrombolysis. Conflict of interest
None.
References 1. Costantino G, Podda GM, Bonzi M, Sbrojavacca R, Gruppo di Autoformazione Metodologica (GrAM) (2013) Italian guidelines on thrombolysis indications in ischemic stroke have been revised after IST-3 trial and Cochrane Revision: cons. Intern Emerg Med 8:651–652
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2. Ricci S, Cenciarelli S, Mazzoli T (2013) Italian guidelines on thrombolysis indications in ischaemic stroke have been revised after IST 3 trial and Cochrane review: PROS. Intern Emerg Med 8:653–654 3. Sacco S, Di Gianfilippo G, Di Napoli M, Santalucia P, Euforbio M, Triggiani L, Cimini N, Ciancarelli I, De Santis F, Olivieri L, Pistoia F, Marini C, Carolei A (2006) L’ictus in Italia: risultati a 5 anni de L’Aquila stroke registry (1994–1998) e confronto con studi comparabili di popolazione nazionali ed internazionali per una politica di gestione programmata della patologia. Riv Neurobiol 2:109–136 4. Sacco S, Stracci F, Cerone D, Ricci S, Carolei A (2011) Epidemiology of stroke in Italy: a review. Int J Stroke 6:219–227 5. IST-3 collaborative group (2012) The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 379:2352–2363 6. SPREAD Italian National Guidelines for Stroke http://www.isospread.it
LETTER TO THE EDITOR
Thrombolysis in the elderly: yes but with caution Simona Sacco • Silvia Ricci • Francesca Pistoia Antonio Carolei
•
Received: 1 June 2014 / Accepted: 9 June 2014 Ó SIMI 2014
Dear Editor We have followed with interest the debate referring to the implementation of the Italian guidelines on thrombolysis in ischemic stroke [1, 2] and would add some further cues. The relevance of looking for an effective and safe acute stroke treatment to elderly patients is beyond question. Stroke is very common in the elderly; in fact, about 35 % of all strokes occur in subjects over 80 years of age [3, 4], and with aging of the population, the number of elderly subjects having strokes will increase worldwide. However, elderly patients were excluded or underrepresented in the randomized-controlled trials of i.v. thrombolysis because an 80 year age limit was an exclusion criterion at that time, that was developed to limit the occurrence of complications, and to increase the chances of a better outcome associated with thrombolysis. Unfortunately, evidence of any benefit in this age group was unobtainable, and for this reason early guidelines recommended thrombolysis only in subjects aged less than 80 years. From that time onward, efforts have been made to overcome that age limit, so that several studies found benefits even in subjects aged 80 years or older [5]. This has led to the modification of the recommendations granting extension of the indications for i.v. thrombolysis to the oldest-old in several national guidelines, including the Italian ones [6]. In principle, we agree that older age should no longer represent a pre-defined exclusion criterion for thrombolysis, but we also suggest that future research and guidelines should move toward identification of robust criteria to S. Sacco (&) S. Ricci F. Pistoia A. Carolei Department of Applied Clinical Sciences and Biotechnology, Institute of Neurology, University of L’Aquila, via Vetoio, 67100 L’Aquila, Italy e-mail: [email protected]
allow a reliable selection of those elderly subjects who may have a true benefit from treatment in the absence of any significant risks. In almost all instances, elderly patients included in the available clinical studies on thrombolysis are those showing, on the basis of physicians’ evaluations, a high likelihood of benefits and a low risk of complications. Future studies should translate into clinical practice the mostly subjective criteria that were used by the clinicians to select subjects included into clinical trials. In addition, we want to underscore that in the IST-3 trial, patients aged [90 years represent a small subset of the overall elderly patients, and the efficacy and safety of the treatment in this specific age group is not reported [5]. Moreover, in the same trial, thrombolysis is associated with high 7-day mortality for intracerebral hemorrhage. In the elderly there is a higher incidence of cerebral small-vessel disease and cerebral microbleeds that may represent markers of increased risk of thrombolysis-related intracerebral hemorrhage. Furthermore, older patients have a relevant burden of medical comorbidities, and up to onethird of them have pre-stroke disability or dementia. The impact of thrombolysis in those circumstances is greatly controversial. Besides, we should keep in mind that elderly patients are those with higher rates of in-hospital complications that are predictors of death and disability, and that then chances of recovery can be hampered by reduced neuronal plasticity, baseline disability, and poorer social supports. Moreover, as thrombolysis is an expensive treatment, in the patients aged [90 years, the cost–benefit ratio is likely to be high, with consequent ethical implications. For all the above reported reasons, we need reliable criteria to select the appropriate candidates for i.v. thrombolysis. Key issues known to be predictive of outcome should help in guiding clinical judgment, leading to
123
Intern Emerg Med
appropriate patient selection. Important factors to be considered are age (80 vs more than 90 years), stroke severity and subtype, pre-stroke disability, dementia, any relevant comorbidity as well as the personal wishes of the subject and family. Future studies should help to develop successful predictive scores, to select the elderly patients who have the greater likelihood to benefit from thrombolysis. Conflict of interest
None.
References 1. Costantino G, Podda GM, Bonzi M, Sbrojavacca R, Gruppo di Autoformazione Metodologica (GrAM) (2013) Italian guidelines on thrombolysis indications in ischemic stroke have been revised after IST-3 trial and Cochrane Revision: cons. Intern Emerg Med 8:651–652
123
2. Ricci S, Cenciarelli S, Mazzoli T (2013) Italian guidelines on thrombolysis indications in ischaemic stroke have been revised after IST 3 trial and Cochrane review: PROS. Intern Emerg Med 8:653–654 3. Sacco S, Di Gianfilippo G, Di Napoli M, Santalucia P, Euforbio M, Triggiani L, Cimini N, Ciancarelli I, De Santis F, Olivieri L, Pistoia F, Marini C, Carolei A (2006) L’ictus in Italia: risultati a 5 anni de L’Aquila stroke registry (1994–1998) e confronto con studi comparabili di popolazione nazionali ed internazionali per una politica di gestione programmata della patologia. Riv Neurobiol 2:109–136 4. Sacco S, Stracci F, Cerone D, Ricci S, Carolei A (2011) Epidemiology of stroke in Italy: a review. Int J Stroke 6:219–227 5. IST-3 collaborative group (2012) The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 379:2352–2363 6. SPREAD Italian National Guidelines for Stroke http://www.isospread.it
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