Risks and Benefits of Thrombolysis in the Elderly

Abstract

Background and purpose

Stroke incidence continues to rise exponentially with age even as temporal trends in some population risk factors increase and others decline. In general, older patients with stroke have worse outcomes compared to their younger counterparts. Stroke severity, concurrent medical problems, prestroke disability, and less-aggressive acute and chronic management are a few contributing factors to account for this poor prognosis. Acute thrombolysis therapy is the only proven treatment in acute ischemic stroke. However, elderly patients have mostly been excluded from acute revascularization studies, due predominantly to their overall poor prognosis and the fear of hemorrhagic complications from these treatments. Despite this, there is no evidence to suggest that the risk benefit ratio of thrombolysis treatment is substantially different in the elderly than in younger ischemic stroke patients.

Summary of review

In this review, we briefly examine the stroke risk factor profile and outcome in the elderly and review the current evidence regarding intravenous and intra-arterial revascularization treatments.

Conclusion

We feel that carefully selected patients who meet eligibility criteria for thrombolysis should not be denied this therapy on the basis of age alone.

Keywords

acute stroke therapy aging cerebral hemorrhage epidemiology stroke prevalence thrombolysis

Introduction

Stroke is a debilitating disease and a leading cause of morbidity and death among adults. Advanced age is a strong predictor of the development of stroke of all types. Stroke incidence exponentially increases with age, doubling for each successive decade after the age of 55 (1, 2). In most studies, the rate of total stroke among patients younger than 45 ranges from 0·1 to 0·3 per 1000 person-years, compared to 12–20 per 1000 person-years in those older than 75 (3).

The aging population is an inevitable result of increased life expectancy and reduced fertility rate in recent decades. By 2025, it is estimated that adults over 65 years of age will comprise 10% of the global population and increases of up to 300% of the elderly population are expected in many developing countries (4). The global occurrence of stroke is therefore projected to rise over the next two decades; this is true even as the age-adjusted incidence of stroke continues to gradually fall. In 2005, there were 16 million reported first-ever strokes; this number is expected to rise to 18 million in 2015 and 23 million people by 2030 (5). Despite the fact that the elderly form a significant and growing segment of acute stroke sufferers, use of intravenous thrombolytic therapy, the only proven treatment for acute ischemic stroke, remains controversial in these patients.

In this review, we briefly examine age as a risk factor for stroke and its effect on outcomes. We then review the current evidence for acute revascularization therapies including intravenous and intra-arterial thrombolytic treatment in the elderly.

Stroke risk and age

In a large population-based cohort of central Auckland, the rate of first-ever stroke increased from less than 1 per 10 000 in those younger than 35 years of age to over 300 per 10 000 at ages 85 and older (6). The Oxford Vascular (OXVASC) study also indicated a 12-fold increase in the incidence of nondisabling and disabling ischemic stroke in the age group of 85 years and older compared to younger population (7). Other studies have also shown a steep rise in the incidence and prevalence of ischemic stroke with each successive decade of life (8, 9). Using age-specific data, the cumulative lifetime risk of stroke, increases by 11-fold between 65 and 90 years of age (10).

Effect of age on stroke outcome

In general, older patients fare worse than younger patients after stroke. Age, however, remains secondary in importance to stroke severity with respect to outcome prediction. Between 50% to 70% of stroke survivors regain functional independence, but 15–30% of patients are disabled and 20% require institutional care at 90 days after stroke onset (11, 12). The two-year mortality rate after first-ever stroke is reported as high as 46% (13). It is well recognized that age is negatively associated with stroke outcome independent of other vascular risk factors (14). Older patients have higher acute and long-term poststroke mortality rates compared to their younger counterparts (15).

Stroke severity, concurrent medical problems, poorer socio-demographic profile, and prestroke disability are a few contributing factors to this difference in prognosis in elderly stroke patients. The European BIOMED study showed that prestroke institutionalization was higher in patients over 80 years of age and that age was a strong and independent determinant of poor three-month functional outcome (16). The multicenter Canadian cohort of hospitalized stroke patients similarly showed that octogenarians have a higher stroke fatality rate, longer duration of hospital stay, and are less likely to be discharged to their original place of residence (17). In a hospital-based study of 486 patients, poststroke cognitive decline was seen in 70% of patients 71–85 years of age compared to 59% of those between 55–70 years of age (14). Relative poststroke social function impairment was also significantly larger in ischemic stroke patients older than 70 years of age. Data from an epidemiological stroke outcome study of over 15 000 patients in the United States suggest that stroke hospitalization in the very elderly, is more likely to result in either death or discharge to a long-term care facility than hospitalization for younger patients (18).

Vascular risk factors and age

Worse clinical outcome following stroke in the elderly can be in part related to a different and perhaps more severe vascular risk factor profile in the elderly. Aging can be thought of as the duration of exposure to different vascular risk factors including an individual's genetic profile, rather than simply a risk factor itself. Ideally, one would conduct epidemiological studies with time-varying covariates to better understand these relationships but these kinds of detailed data are rarely available. The incidence of established cerebrovascular risk factors such as hypertension, diabetes mellitus, atrial fibrillation, and dyslipidemia increase with age (19, 20). These risk factors have been associated with an increased mortality rate themselves (21). Hence, a reduction in their incidence in octo- and nonagenarians, due to survival effect, reflects continuous natural selection of individuals with the fewest cardiovascular risk factors. In contrast, smoking, alcohol consumption, and obesity are more prevalent among younger stroke patients suggesting a higher impact of lifestyle on risk of stroke in younger patients (22).

Age-specific changes in vascular risks profile vary between men and women (22). The ischemic stroke female/male incidence ratio increases with age. Older age at stroke onset is suspected to be a factor in the poorer stroke outcomes seen in women (23, 24). A population-based study in Sweden revealed that women over the age of 75 have a 50% higher stroke incidence than men (25). A similar disproportionate increase in stroke rates in elderly women was seen in the OXVASC (26) and the Greater Cincinnati-Northern Kentucky Stroke studies (27). These differences may be related to the longer life expectancy of women and possibly hormonal and immune-related factors (28).

Hypertension, the single most important modifiable vascular risk factor for stroke, is highly age dependent. Data from the Framingham heart study suggest that individuals who are normotensive at age 55 have a 90% lifetime risk of developing stage 1 hypertension (BP 140–159/90–99 mmHg) and a 40% lifetime risk of developing stage 2 hypertension (BP ≥ 160/≥100 mmHg) (29). A second report, also from the Framingham cohort, suggest a progressive increase in the frequency of development of hypertension over time among patients older than 65 years of age (30). A similar progression was found in younger individuals, but at much lower rates. Although treatment has been shown to be effective (31, 32), hypertension is commonly underdiagnosed and inadequately treated in the elderly population (33). Diabetes mellitus is a common risk factor for stroke. Patients with diabetes mellitus or with hyperglycemia at presentation fare worse than those without. Patients with diabetes mellitus have a greater risk of complications and stroke recurrence. Diabetes mellitus may coexist as part of the metabolic syndrome (34), which increases with aging (35).

Aging is associated with common risk states for stroke. Atrial fibrillation is more common among the elderly (19, 36) and associated with threefold to fourfold increased risk of stroke after adjustment for other risk factors (37). Both prevalence of atrial fibrillation and its attributable risk of stroke increases with age (20, 38). Similarly, the prevalence of carotid stenosis rises with age and while most carotid disease remains asymptomatic, it accounts for an increasing proportion of ischemic stroke cases in the elderly (39). An age-based analysis of the North American Symptomatic Carotid Endarterectomy Trial results, showed an increased risk of ipsilateral stroke with aging for any degree of carotid stenosis (40).

Thrombolysis and outcome in the elderly

Thrombolysis remains the most relevant treatment for acute ischemic stroke. Despite this, it has not been systematically studied in the elderly. The majority of acute stroke thrombolysis trials excluded patients greater than 80 years of age. In only six published trials, treatment was administered to very elderly patients. Thus, only a limited number of patients greater than 80 were treated with tissue plasminogen activator (tPA) in the context of a randomized controlled trial (RCT) (41–47). A much larger number of elderly patients have been included in postmarketing tPA registries. The Safe Implementation of Treatment in Stroke-International Stroke Register (SITS-ISTR) registry includes approximately 1800 patients over the age of 80 (48).

Urokinase and streptokinase

One trial in the Chinese literature reported on the use of intravenous urokinase in ischemic stroke patients without an upper age limit (49). Because alteplase (tPA) is the only licensed treatment for acute ischemic stroke, these data are less relevant to current practice (43).

Two RCTs of streptokinase (SK; multicenter acute stroke trial-Europe (MAST-E) and multicenter acute stroke trial-Italy (MAST-I)) included elderly patients (41, 42). The MAST-I was a RCT of 622 patients, presenting within six-hours of acute ischemic stroke symptoms. In a 2 × 2 factorial design, patients either received 1·5 MU SK, 300 mg/day aspirin for 10 days, both active treatments, or neither. A total of 212 patients in MAST-I were older than 75 years of age, of whom 117 received SK treatment. The 10-day mortality rate in this sub-group was 35% vs. 10·5% in the control group (aspirin or no treatment). In the sub-group analysis, time from onset of ischemic symptoms to treatment and not age was the only independent factor predictive of early mortality.

The MAST-E (42) was a double-blind, RCT of SK therapy vs. placebo in 310 patients who presented within six-hours of moderate-to-severe ischemic symptoms in the territory of the middle cerebral artery. There was no difference in the mean age of thrombolysed patients (68·7, range = 22–92) as compared to the placebo group (69·8, range = 28–94). Similarly, in the post hoc analysis of the MAST-E database, there was no difference in the mean age of all patients who developed hemorrhagic transformation (69·1 (22–92) vs. 69·9 (32–94), P = 0·63) and symptomatic intracranial hemorrhage (sICH) (70·6 (38–92) vs. 69·1 (22–94), P = 0·50) as compared to those who did not (50). Furthermore, in the SK treatment arm, advanced age was not a predictor of symptomatic hemorrhagic transformation. The prospective Thrombolysis in Acute Stroke Pooling Project was established to examine the aggregate data from 1292 patients enrolled in four SK randomized trials and to identify factors influencing the effect of thrombolysis (51). In this study, advanced age and severity of initial deficit appeared to have no impact on the deleterious side effects of SK. In contrast, concomitant use of aspirin, higher dose of SK, and delayed time from onset to therapy predicted poor outcome.

Tissue plasminogen activator

The National Institute of Neurological Disorders (NINDs) and Stroke recombinant tissue plasminogen activator (rtPA) Stroke Trial (47) was a randomized, double-blind trial or rtPA vs. placebo within three-hours of stroke onset. The trial had two parts: part 1 (in which 291 patients were enrolled) assessed the clinical activity of within 24 h of symptom onset; and part 2 (in which 333 patients were enrolled) assessed three-months clinical outcome. The initial NINDs protocol stated an upper age limit of 80 years. However, this was removed after 188 patients had been recruited into part A of the trial, and thereafter, 42 patients over the age of 80 were randomized. There was no significant difference in neurological improvement in 24 h, although a significant benefit in favor of thrombolysis was noted at three-months for all four-outcome measures. A post hoc analysis of the combined results of parts 1 and 2 showed that t-PA treatment was independently and strongly associated with an increased likelihood of favorable outcome in three-months in all sub-groups (52). Analysis of the 49 patients aged > 75 with admission National Institutes of Health Stroke Scale (NIHSS) > 20 showed that tPA therapy markedly improved outcome on Barthel and Glasgow scales and reduced the number of patients with severe neurological deficit as measure by the NIHSS and modified Rankin Scale (mRS).

The Alteplase ThromboLysis for Acute Non-interventional Therapy in Ischemic Stroke (ATLANTIS) and The European Cooperative Acute Stroke Study (ECASS)I, II, and III trials specifically included patients between 18 and 80 years of age (53–55). A secondary analysis of the ECASS II data showed that increasing age was associated with development of sICH (odds ratio (OR) 1·04 (1·00–1·08), P = 0·04) (56). In this analysis, 19·7% of patients between 71 and 80 years of age who received intravenous (i.v.) tPA had evidence of parenchymal hemorrhage on follow-up scan, as compared to only 2·5% in the aged matched sub-group receiving placebo. However, the effect of age on development of sICH was significantly smaller than the other factors, such as a history of congestive heart failure and extent of parenchymal hypoattenuation on baseline computed tomography scan. The sub-group analysis of the ECASS III data showed that treatment with alteplase was as effective in achievement of favorable outcome (mRS 0–1), in older patients (≥65, OR = 1·15 (0·8–1·64)) similar to their younger counterparts (<65 years, OR = 1·61 (1·05–2·48); P = 0·23). However, similar to the ECASS II results, age ≥ 65 was an independent predictor of development of sICH (<65 years: 0·74, 0·28–1·96; ≥65 years: 5·79, 2·18–15·39; P = 0·004) (57). The license for alteplase treatment in the European Union is restricted to patients younger than 80 years of age (55, 58). An upper age limit is not included in the most recent American Heart Association acute stroke thrombolysis guidelines (59).

The Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) was a RCT of intravenous alteplase vs. placebo in patients presenting within three- to six-hours of onset without an upper age limit (46). The mean age of patients who received thrombolysis (72·2 years) was not different from placebo group (70·9 years). Although a sub-group analysis of outcome in patients over age 80 in EPITHET has not been reported, a multivariable analysis of all patients in the treatment group did not show a correlation between advanced age and increased 90-day mortality (1·03, 0·98–1·07; P = 0·268) (46).

In a pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials, looking at the relationship between time from stroke onset and thrombolysis treatment to favorable outcome, advanced age along with high NIHSS at admission, diastolic blood pressure, and previous hypertension were identified as potential confounders. In the final analysis, the only significant factor to predict favorable outcome remained the interaction between thrombolysis treatments and the time from stroke onset to treatment (60).

Thrombolysis-related hemorrhagic transformation in the elderly

Symptomatic intracerebral hemorrhage (sICH) is the most frequently feared complication of thrombolysis, and when it occurs, is associated with poor outcome (61). Several factors have been postulated to increase the risk of sICH after thrombolysis in the elderly. Age-related cerebral amyloid angiopathy (62), hypertensive angiopathy (63), fragile vasculature, and impaired rate of systemic tPA clearance (64) are some potential mechanisms for increased hemorrhage. The results of the small cohort studies have shown inconsistent findings when comparing symptomatic hemorrhage, mortality rates, and the overall clinical outcomes between i.v. rtPA-treated stroke patients over age 80 and those younger (65–69). One issue that persists in the stroke literature is an inconsistent definition of sICH, which impairs comparisons between studies. Symptomatic hemorrhage in the NINDS trial was defined as any hemorrhage resulting in an increase in the NIHSS from baseline or death within seven-days (47). In contrast, any hemorrhage plus a neurological deterioration of four points or more on the NIHSS from baseline, or from the lowest NIHSS value after baseline to seven-days or hemorrhage causing death was the definition used for sICH in ECASS II trial (56). The same clinical deterioration associated with a local or remote parenchymal hemorrhage type II (70) on the 22–36 h posttreatment imaging scan was considered symptomatic in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST). Thus, it must be noted that the SITS-MOST criteria for sICH only included more severe hemorrhages.

A multicenter Italian prospective study reported a higher mortality rate in the elderly sub-group (≥80 years of age) but no significant difference in the rate of symptomatic hemorrhage (by ECASS-II definition) or poor outcome (71). The NINDS definition for sICH was used in the Canadian Activase for stroke Effectiveness Study (CASES) (72). This study compared clinical outcome in 242 octogenarian with 28 nonagenarians treated with i.v. tPA and did not show a significant difference between the groups in either the rate of sICH (4% vs. 9%; P = 0·359), 90-day mortality (33% vs. 52%; P = 0·087) or 30-day functional outcome (mRS ≤ 1; 26% vs. 30%; P = 0·647). Although a nonsignificant trend toward a higher 90-day mortality was noted in the nonagenarians in the CASES registry.

The age-based outcome assessment in patients participating in the neuroprotection trials within the Virtual International Stroke Trials Archive (VISTA), showed improved neurological and functional outcome in thrombolysed patients from 51 to 90 years of age relative to those not treated with tPA (73). The association between thrombolysis and favorable outcome occurred independent of age and with similar magnitude among young (≤80) (OR 1·42 (1·26–1·59), P < 0·0001) and elderly (>80; OR 1·34 (1·05–1·70), P = 0·002) patients. The authors concluded that despite the expected poorer outcomes among the elderly patients, independent of any treatment effect, these patients benefit from thrombolysis treatment. Rate of sICH was not reported in VISTA as posttreatment imaging was not routinely performed in neuroprotection trials.

The large prospective observational study of thrombolysis outcome in the SITS-ISTR compared the neurological and functional outcome in 1831 thrombolysed patients over the age 80 with that of 19 411 patients ≤80 (48). The overall rate of sICH (SITS-MOST definition) was not increased with thrombolysis in the >80-year-old group (1·8%) as compared to those ≤80 (1·7%, P = 0·70) after adjustment for other risk factors. However, the study did indicate a progressive risk of sICH with each successive decade from <60 to 80 with no difference between the patients in the seventh and eighth decades. Despite limited data, the risk of sICH seemed to decrease in patients > 90 years of age perhaps because of careful patient selection or age-related self-selection (74). Similar to the results of the VISTA registry, the SITS-ISTR data also showed a higher mortality rate at three-months and a lower rate of favorable outcome (mRS 0–2) in the octogenarians compared with younger patients. The poor thrombolysis outcome in the elderly is thought to be multifactorial and may be related to the greater stroke severity, prestroke dependency, more severe vascular risk factor profile, higher chance of in-hospital complications such as pneumonia, and not intrinsically due to the complications of thrombolysis. Two large systematic reviews of observational studies comparing outcomes in the thrombolysed patients over the age 80 with those younger than 80 have been published (75, 76), neither of these studies showed an increased likelihood of sICH in thrombolysed patients in the elderly sub-groups. However, both studies highlighted significant differences between the young and old patients in their baseline characteristics to the disadvantage of older patients. These differences likely accounted for the threefold higher mortality rate and poor favorable outcomes in the elderly patients.

Our understanding of the safety and efficacy of thrombolysis will be enhanced when the results of ongoing thrombolysis trials become available. The Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke (DIAS-3 and DIAS-4) are both ongoing phase III RCTs of desmoteplase vs. placebo in ischemic stroke patients presenting between three- and nine-hours after symptom onset (77). The upper age limit for enrollment in both studies is 85 years. The Thrombolysis in Elderly Stroke Patients in Italy is an ongoing phase III multicenter study of ischemic stroke patients over the age 80 presenting within three-hours of onset (78). Patients are randomized 1:1 to receive either alteplase or conservative treatment. The main objective of the study is to show that thrombolysis will improve clinical outcome with favorable benefit/risk ratio. Finally, the much larger Third International Stroke Trial is a randomized multicenter study of thrombolysis within six-hours of ischemic stroke symptoms onset (79). The trial does not have an upper age limit for enrollment and the results will provide better evidence regarding efficacy of thrombolysis and the risk of sICH in the elderly population.

Intra-arterial and endovascular treatment trials in the elderly

Although intra-arterial (IA) thrombolytic treatment has been used in acute ischemic stroke for many years (80), it is not an approved therapy by the US Food and drug Administration. Aggressive IA fibrinolytic treatments and endovascular thrombus removal/retrieval measures are based on the hypothesis that effective and rapid recanalization leads to improved reperfusion in the affected ischemic regions. These approaches have been justified by a series of studies showing that recanalization is associated with reasonable rates of good functional outcome and reduced risk of stroke-related mortality (81). Data on safety and efficacy of intra-arterial or any other endovascular treatments are limited in the elderly population.

Patients aged ≥85 were excluded from the Prolyse in Acute Cerebral Thromboembolism (PROACT) I and II randomized trials (82, 83). In both studies, intra-arterial delivery of recombinant pro-urokinase significantly increased the angiographic recanalization rate at the cost of an increased risk of early neurological deterioration related to intracranial hemorrhage. Advanced age was not a predictor of increased sICH in PROACT trials; in a retrospective analysis of 76 consecutive patients between 35 and 83 years of age with ischemic stroke who received intra-arterial urokinase (84). A comparative analysis of outcome in patients >80 vs. those <80 receiving IA urokinase in a consecutive registry showed similar revascularization rate (thrombolysis in myocardial infarction scale (TIMI) 2–3) in the older sub-group (67%) compared to the younger patients 79%, P = 0·10 (85). Older patients had a significantly higher mortality rate (43%) relative to their younger counterparts (20%) but had similar rates of sICH (7% vs. 8%) or any ICH (39% vs. 37%).

The safety and feasibility of a combined i.v.-IA thrombolysis approach was assessed in the Interventional Management of Stroke (IMS) study I and II (86, 87). A pooled analysis of IMS I and II studies showed a high (74%) rate of partial or complete revascularization with the combined i.v.-IA therapy and good outcomes on both reperfusion (Thrombolysis in Cerebral Infarction (TICI) 2 to 3: P = 0·0004; TICI 2B-3: P = 0·0002) and recanalization (arterial occlusive lesion 2 to 3: P = 0·03) scales (88). The ongoing IMS-III study is a randomized multicenter trial comparing the efficacy of combined i.v./IA approach to the standard i.v. tPA therapy alone (89). All three studies have excluded patients over the age 80 and aged-based analysis have not been reported on any them.

The Mechanical Embolus Removal in Cerebral Ischemia (MERCI) pilot study (90) and the multi-MERCI trial (91) were both prospective single-arm studies, evaluating the safety and efficacy of mechanical thrombectomy with or without IA thrombolysis in patients with large vessel intracranial occlusion. Patients with ischemic stroke up to 8 h of symptom onset without an upper age limit were included. In a pooled analysis of the 305 patients enrolled in MERCI-1 and multi-MERCI, younger age, final revascularization rate, and lower baseline NIHSS were independent predictors of good outcome (92). Final revascularization status was a much stronger predictor of favorable clinical outcomes (OR, 20·4 (7·7–53·9)) as compared to age (OR, 0·96 (0·95–0·98)). Similar to other studies, advanced age was strongly predictive of 90-day mortality in the pooled analysis. Elderly patients (≥80) were excluded and age-based outcomes were not reported from the Penumbra Stroke trial (93).

Conclusion

Stroke is a condition of advanced age. It is often the last and final illness. Although advanced age in isolation should not be regarded as a contraindication for acute intervention, it must be noted that age-related vascular and brain parenchymal changes do impose a greater vulnerability in this sub-group, which could increase the rate of thrombolysis or other procedural complications. Careful pretreatment selection plays a particularly important role in this group. The stroke physician must exercise significant judgment in treating the very elderly. Much remains to be learned and the selected elderly ought to be considered for clinical trials of acute stroke therapy.

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