A new analysis of nearly 30,000 stroke patients has shown thrombolysis treatment to be helpful for people aged 80 years and older, who show functional outcomes similar to those of much younger stroke patients after 90 days, and comparable mortality.
The findings, published online Nov. 24 in BMJ (BMJ 2010;341:c6046) and using data from the Safe Implementation of Treatment in Stroke–International Stroke Thrombolysis Register (SITS-ISTR) and the Virtual International Stroke Trials Archive (VISTA), suggest that treatment with intravenous alteplase should not be withheld on the basis of age alone, despite current European licensing rules and guidelines that restrict the use of recombinant tissue plasminogen activators to stroke victims under age 80.
The reason for the European Medicine Agency’s alteplase restriction was concern over a potential increased risk of symptomatic, treatment-related intracranial hemorrhage in older people, and the fact that there was not yet enough clinical evidence for the safety and effectiveness of alteplase and other recombinant tissue plasminogen activators in this patient group, as older people had been under-represented in clinical trials.
Yet, as the BMJ study’s investigators, led Dr. Kennedy R. Lees of the University of Glasgow (U.K.), noted in their analysis, some 30% of stroke victims are over age 80, and the percentage of people in this age group is growing in developed nations. In the study Dr. Lees and his colleagues built upon years of increasing speculation that thrombolysis, administered within 3 hours after stroke, was effective and safe in this patient group too, with clinicians increasingly administering it and reporting good outcomes.
The SITS registry provided Dr. Lees and his colleagues an ongoing source of data on elderly patients who had received thrombolysis. Of the 29,500 stroke patients available for analysis, 3,439 were older than age 80 (mean age 84.6 years). A total of 23,334 patients had undergone thrombolysis with alteplase (mean 145 minutes after stroke onset). Data on 6,166 patients who did not receive thrombolysis but received placebo or a neuroprotective agent were available from the VISTA registry, and these patients served as controls. Median baseline stroke severity was equal for patients and controls (median National Institutes of Health (NIH) stroke scale score 12). A total of 272 patients from both groups were removed from the analysis for missing stroke severity data, leaving data on 29,228 available for final analysis.
Dr. Lees and his colleagues found that functional outcomes 90 days post stroke, measured by modified Rankin scale scores, which measure debilitation, were significantly better in patients who received thrombolysis, and that this was true in patients both younger than 80 years (odds ratio 1.6) and over 80 years (OR 1.4). The number needed to treat for one more elderly patient to achieve a favorable Rankin score of 0-2 (no disability or slight disability that does not affect independence) at 3 months was 8.2, compared with 8.5 for younger patients.
Rates of intracerebral hemorrhage – avoidance of which was the original rationale for denying thrombolysis to older patients – were shown to be only slightly increased in the older patients, depending on how the hemorrhage was defined and diagnosed. Symptomatic hemorrhage occurred in 2.5% of the 80 and older group and 1.9% of the younger patients, according to a SITS definition, and in 11% vs. 8.3%, respectively, when measured according to an NIH definition. However, the odds ratio for mortality was almost exactly the same – 0.89 (0.76-1.04) in elderly patients receiving thrombolysis, compared with 0.87 (0.79-0.95) in younger patients.
The investigators saw no benefit associated with thrombolysis in patients older than 90 or younger than 40. However, they noted, "the small number of patients in these groups greatly reduced statistical power for these analyses, and the trends mostly followed the same pattern as for intermediate ages." They concluded that clinical treatment guidelines "should be revised to remove the age restriction in use of intravenous alteplase for acute ischemic stroke. Age alone should not be a barrier to treatment."
In an editorial accompanying Dr. Lees and colleagues’ article, neurologist Laurent Derex of Inserm and the Neurological Hospital in Lyon, France, characterized the results as "quite robust," noting that the odds ratios were consistent across all 10-year age ranges. Moreover, Dr. Derex said, "elderly patients may be especially vulnerable to subjective judgments of the benefit of optimal stroke care, particularly when medical resources are limited."
But Dr. Derex also cautioned that the study’s nonrandomized design was not ideal, as the investigators themselves acknowledged. "As a post hoc analysis of a thrombolysis registry, the study is prone to selection bias," Dr. Derex wrote. "If the elderly patients with stroke included in this registry were more carefully selected for administration of intravenous recombinant tissue plasminogen activator, the findings would be less generalizable to all elderly patients. ... Ongoing randomized controlled thrombolytic trials that include patients aged over 80 years should yield more robust conclusions" (BMJ 2010; 341:c5891)