Thrombolytic Therapy is Indicated for Patients Over 75 Years
Thrombolytic Therapy is Indicated for Patients Over 75 Years
Although the benefits of thrombolytic therapy are well established in patients younger than age 75 years with acute ST-elevation myocardial infarction, the value of thrombolytic treatment in patients 75 years of age or older remains controversial. This is due in part to conflicting data from clinical trials and observational studies and in part because of concerns about increased risk for major bleeding complications in the very elderly, particularly intracranial hemorrhage. However, in a recent meta-analysis based on data from 3322 patients aged 75 years or older presenting with ST-elevation myocardial infarction within 6 hours of symptom onset, thrombolytic therapy was associated with an absolute mortality reduction of 3.4% (26.0% vs. 29.4%), an effect similar to that seen in younger patients. In addition, although the risk of stroke increased with age, the absolute excess risk of stroke in patients older than age 75 years receiving thrombolytic treatment was <1%, and there was no age-associated excess in the risk of other major bleeding complications. These findings indicate that thrombolytic therapy is beneficial in carefully selected elderly patients with acute myocardial infarction and that the risk of major adverse events is acceptably low.
In 1999 there were approximately 829,000 admissions to short-stay hospitals in the United States with a primary discharge diagnosis of acute myocardial infarction (MI). Of these, 509,000 (61.4%) occurred in the 12.6% of the US population over age 65 years, and 305,000 (36.8%) occurred in the 6.1% of the US population aged 75 years or older. Moreover, patients older than age 65 years account for approximately 85% of all deaths attributable to acute MI and about 60% of deaths occur in persons older than age 75 years. Thus, acute MI disproportionately affects the elderly, and case-fatality rates increase strikingly with advancing age.
In the next 30 years there is projected to be a doubling in size of the US population older than age 65 years from its current level of approximately 35 million to approximately 70 million. In accordance with this rise, it may be anticipated that the number of older persons suffering acute MI will increase dramatically. It is therefore essential to develop effective strategies for both the prevention and treatment of acute MI in the elderly.
In the late 1970s and 1980s, the introduction of thrombolytic therapy revolutionized the management of patients with acute MI, especially those presenting with ST-segment elevation in multiple electrocardiographic leads. Although there is compelling evidence that thrombolytic therapy reduces infarct size and improves survival in patients up to 75 years of age presenting within 12 hours of MI onset, the efficacy of thrombolysis in patients older than age 75 years remains controversial. This article reviews the evidence supporting the use of thrombolytic therapy in persons older than 75 years of age with acute ST-segment elevation MI.
Table I summarizes pooled data from the five major placebo-controlled trials of thrombolytic therapy. Although the relative mortality reduction was greater in younger than in older patients (25.7% vs. 16.9%), the absolute mortality reduction was greater in the older subgroup (2.2% in younger vs. 3.5% in older). Thus, 45 younger patients must be treated (number needed to treat) to prevent one death, compared with only 29 older patients. Although the data in Table I strongly suggest that thrombolytic therapy is beneficial in older adults, the analysis does not specifically address the value of thrombolysis in patients older than age 75 years. In the Gruppo Italiano Per Lo Studio Della Streptochinasi Nell'Infarto Miocardico (GISSI-1) trial, which included 1215 patients aged 75 years or older randomized to intravenous streptokinase or placebo, mortality was 28.9% in patients who received streptokinase compared with 33.1% in those receiving placebo (absolute risk reduction, 4.2%; number needed to treat,
24). Although the absolute benefit from streptokinase was greater in patients older than age 75 years than in those younger than age 65 years, the difference was not statistically significant, reflecting the smaller size of the elderly cohort.
In the Second International Study of Infarct Survival (ISIS-2), 401 patients older than age 80 years were randomized to receive streptokinase or placebo. As shown in Table II , mortality was reduced from 34.2% in the placebo arm to 20.1% in the streptokinase arm, a relative risk reduction of 41% and an absolute risk reduction of 14.1%. Of particular note is that both the relative and absolute risk reductions were greater in patients older than age 80 years than in any other age group, and that the benefits occurred without an increase in the risk of intracranial hemorrhage, other strokes, major bleeding, or hypotension. Although octogenarians enrolled in ISIS-2 comprised a selected patient population, the data clearly demonstrate that even very elderly patients may derive substantial benefit from thrombolytic treatment.
Despite the strength of the evidence from prospective randomized clinical trials (RCTs), other analyses and observations have cast doubt on the value of thrombolysis in the very elderly. In 1994, the Fibrinolytic Therapy Trialists (FTT) reported the results of a meta-analysis based on all available data from large placebo-controlled RCTs of thrombolytic therapy. This analysis found that although the absolute reduction in mortality was similar in patients aged 75 years and older to those aged 55 years or younger, the difference was not statistically significant in older patients. An important limitation of this analysis was that it included a substantial number of elderly patients who either presented "late" (i.e., more than 12 hours after symptom onset) or who did not have evidence for ST-elevation or left bundle branch block on the admission electrocardiogram. A recent reanalysis of the FTT data, designed to evaluate thrombolytic therapy in patients presenting within 6 hours of symptom onset with ST-elevation or left bundle branch block, showed that patients in all age groups derived significant benefit from thrombolytic treatment ( Table III ). Indeed, among 3322 patients older than 75 years of age included in the analysis, the absolute mortality reduction was similar to that seen in patients aged 55-74 years and was more than two-fold greater than that seen in patients younger than age 55 years.
A second factor that has fueled uncertainty about the value of thrombolysis in the very elderly has been the publication of several observational studies suggesting that thrombolytic therapy applied on a population-wide basis may be associated with either no benefit or possibly even harm. However, two points are worth noting. First, it is highly likely that the lack of benefit from thrombolytic therapy observed in these studies is related to poor patient selection; that is, failure to observe the strict criteria for use of thrombolytic drugs supported by data from RCTs. The message, therefore, is that thrombolytic therapy should not be used indiscriminately in the very elderly; rather, careful patient selection is mandatory. The second point is that in the only one of these observational studies that examined long-term outcomes, thrombolytic therapy was associated with substantially better 12-month survival than a strategy of no reperfusion (i.e., benign neglect). Moreover, improved late survival was evident not only in patients aged 75-84 years, but even in those aged 85 years or older (Figure). Furthermore, 1-year survival following thrombolytic treatment was equivalent to that following percutaneous coronary intervention in hospitals equipped to perform either procedure.
(Enlarge Image)
Reperfusion therapy in the elderly: 1-year mortality outcomes in Medicare Heart aries. Horizontal bars indicate outcomes relative to no reperfusion therapy. Both assign sis and percutaneous transluminal coronary angioplasty (PTCA) are associated with improved survival at 1 year in all age groups. LBBB=left bundle branch block Reprinted with permission from J Am Coll Cardiol. 2000;36:366-374.
Apart from concerns about the efficacy and effectiveness of thrombolytic therapy in the very elderly, a factor that often deters clinicians from using these drugs is fear of major bleeding complications, particularly intracranial hemorrhage. Although data from the FTT analysis do indicate that the risk of stroke following acute MI increases with age (whether or not a thrombolytic agent is administered), the absolute excess risk of stroke in patients older than age 75 years is less than 1%5 ( Table IV ). Moreover, the risk of major bleeding attributable to thrombolytic therapy is low in all age groups (≤1%), and older age per se is not a marker for an increased risk of major bleeding ( Table V ). Finally, as shown in Table VI , older age is only one among many risk factors for intracranial hemorrhage in patients undergoing thrombolytic treatment, with an effect size similar to that associated with African-American race, female gender, low body weight, and use of tissue plasminogen activator vs. other thrombolytic agents. It makes no more sense to withhold thrombolytic therapy in patients older than age 75 years than it would to withhold this life-saving treatment in other major demographic groups, such as women and African Americans.
Based on high-quality evidence from numerous prospective RCTs, thrombolytic therapy is clearly beneficial in carefully selected elderly patients with acute ST-elevation MI presenting within 6 hours of symptom onset. Although older age is a marker for increased risk of hemorrhagic stroke, the absolute risk is small and age is only one of several risk factors for stroke.
Therefore, concerns about the risk of stroke and major bleeding in elderly patients are unfounded, and these considerations should not preclude the use of thrombolytic treatment in the very elderly. Considering the totality of evidence currently available regarding the use of thrombolytic therapy in patients aged 75 years or older with ST-elevation MI, the American College of Cardiology/American Association guidelines a class IIa indication to such treatment, indicating that the weight of evidence/opinion is in favor of its usefulness and efficacy. It is my view that this recommendation is fully justified and appropriate.
Although the benefits of thrombolytic therapy are well established in patients younger than age 75 years with acute ST-elevation myocardial infarction, the value of thrombolytic treatment in patients 75 years of age or older remains controversial. This is due in part to conflicting data from clinical trials and observational studies and in part because of concerns about increased risk for major bleeding complications in the very elderly, particularly intracranial hemorrhage. However, in a recent meta-analysis based on data from 3322 patients aged 75 years or older presenting with ST-elevation myocardial infarction within 6 hours of symptom onset, thrombolytic therapy was associated with an absolute mortality reduction of 3.4% (26.0% vs. 29.4%), an effect similar to that seen in younger patients. In addition, although the risk of stroke increased with age, the absolute excess risk of stroke in patients older than age 75 years receiving thrombolytic treatment was <1%, and there was no age-associated excess in the risk of other major bleeding complications. These findings indicate that thrombolytic therapy is beneficial in carefully selected elderly patients with acute myocardial infarction and that the risk of major adverse events is acceptably low.
In 1999 there were approximately 829,000 admissions to short-stay hospitals in the United States with a primary discharge diagnosis of acute myocardial infarction (MI). Of these, 509,000 (61.4%) occurred in the 12.6% of the US population over age 65 years, and 305,000 (36.8%) occurred in the 6.1% of the US population aged 75 years or older. Moreover, patients older than age 65 years account for approximately 85% of all deaths attributable to acute MI and about 60% of deaths occur in persons older than age 75 years. Thus, acute MI disproportionately affects the elderly, and case-fatality rates increase strikingly with advancing age.
In the next 30 years there is projected to be a doubling in size of the US population older than age 65 years from its current level of approximately 35 million to approximately 70 million. In accordance with this rise, it may be anticipated that the number of older persons suffering acute MI will increase dramatically. It is therefore essential to develop effective strategies for both the prevention and treatment of acute MI in the elderly.
In the late 1970s and 1980s, the introduction of thrombolytic therapy revolutionized the management of patients with acute MI, especially those presenting with ST-segment elevation in multiple electrocardiographic leads. Although there is compelling evidence that thrombolytic therapy reduces infarct size and improves survival in patients up to 75 years of age presenting within 12 hours of MI onset, the efficacy of thrombolysis in patients older than age 75 years remains controversial. This article reviews the evidence supporting the use of thrombolytic therapy in persons older than 75 years of age with acute ST-segment elevation MI.
Table I summarizes pooled data from the five major placebo-controlled trials of thrombolytic therapy. Although the relative mortality reduction was greater in younger than in older patients (25.7% vs. 16.9%), the absolute mortality reduction was greater in the older subgroup (2.2% in younger vs. 3.5% in older). Thus, 45 younger patients must be treated (number needed to treat) to prevent one death, compared with only 29 older patients. Although the data in Table I strongly suggest that thrombolytic therapy is beneficial in older adults, the analysis does not specifically address the value of thrombolysis in patients older than age 75 years. In the Gruppo Italiano Per Lo Studio Della Streptochinasi Nell'Infarto Miocardico (GISSI-1) trial, which included 1215 patients aged 75 years or older randomized to intravenous streptokinase or placebo, mortality was 28.9% in patients who received streptokinase compared with 33.1% in those receiving placebo (absolute risk reduction, 4.2%; number needed to treat,
24). Although the absolute benefit from streptokinase was greater in patients older than age 75 years than in those younger than age 65 years, the difference was not statistically significant, reflecting the smaller size of the elderly cohort.
In the Second International Study of Infarct Survival (ISIS-2), 401 patients older than age 80 years were randomized to receive streptokinase or placebo. As shown in Table II , mortality was reduced from 34.2% in the placebo arm to 20.1% in the streptokinase arm, a relative risk reduction of 41% and an absolute risk reduction of 14.1%. Of particular note is that both the relative and absolute risk reductions were greater in patients older than age 80 years than in any other age group, and that the benefits occurred without an increase in the risk of intracranial hemorrhage, other strokes, major bleeding, or hypotension. Although octogenarians enrolled in ISIS-2 comprised a selected patient population, the data clearly demonstrate that even very elderly patients may derive substantial benefit from thrombolytic treatment.
Despite the strength of the evidence from prospective randomized clinical trials (RCTs), other analyses and observations have cast doubt on the value of thrombolysis in the very elderly. In 1994, the Fibrinolytic Therapy Trialists (FTT) reported the results of a meta-analysis based on all available data from large placebo-controlled RCTs of thrombolytic therapy. This analysis found that although the absolute reduction in mortality was similar in patients aged 75 years and older to those aged 55 years or younger, the difference was not statistically significant in older patients. An important limitation of this analysis was that it included a substantial number of elderly patients who either presented "late" (i.e., more than 12 hours after symptom onset) or who did not have evidence for ST-elevation or left bundle branch block on the admission electrocardiogram. A recent reanalysis of the FTT data, designed to evaluate thrombolytic therapy in patients presenting within 6 hours of symptom onset with ST-elevation or left bundle branch block, showed that patients in all age groups derived significant benefit from thrombolytic treatment ( Table III ). Indeed, among 3322 patients older than 75 years of age included in the analysis, the absolute mortality reduction was similar to that seen in patients aged 55-74 years and was more than two-fold greater than that seen in patients younger than age 55 years.
A second factor that has fueled uncertainty about the value of thrombolysis in the very elderly has been the publication of several observational studies suggesting that thrombolytic therapy applied on a population-wide basis may be associated with either no benefit or possibly even harm. However, two points are worth noting. First, it is highly likely that the lack of benefit from thrombolytic therapy observed in these studies is related to poor patient selection; that is, failure to observe the strict criteria for use of thrombolytic drugs supported by data from RCTs. The message, therefore, is that thrombolytic therapy should not be used indiscriminately in the very elderly; rather, careful patient selection is mandatory. The second point is that in the only one of these observational studies that examined long-term outcomes, thrombolytic therapy was associated with substantially better 12-month survival than a strategy of no reperfusion (i.e., benign neglect). Moreover, improved late survival was evident not only in patients aged 75-84 years, but even in those aged 85 years or older (Figure). Furthermore, 1-year survival following thrombolytic treatment was equivalent to that following percutaneous coronary intervention in hospitals equipped to perform either procedure.
(Enlarge Image)
Reperfusion therapy in the elderly: 1-year mortality outcomes in Medicare Heart aries. Horizontal bars indicate outcomes relative to no reperfusion therapy. Both assign sis and percutaneous transluminal coronary angioplasty (PTCA) are associated with improved survival at 1 year in all age groups. LBBB=left bundle branch block Reprinted with permission from J Am Coll Cardiol. 2000;36:366-374.
Apart from concerns about the efficacy and effectiveness of thrombolytic therapy in the very elderly, a factor that often deters clinicians from using these drugs is fear of major bleeding complications, particularly intracranial hemorrhage. Although data from the FTT analysis do indicate that the risk of stroke following acute MI increases with age (whether or not a thrombolytic agent is administered), the absolute excess risk of stroke in patients older than age 75 years is less than 1%5 ( Table IV ). Moreover, the risk of major bleeding attributable to thrombolytic therapy is low in all age groups (≤1%), and older age per se is not a marker for an increased risk of major bleeding ( Table V ). Finally, as shown in Table VI , older age is only one among many risk factors for intracranial hemorrhage in patients undergoing thrombolytic treatment, with an effect size similar to that associated with African-American race, female gender, low body weight, and use of tissue plasminogen activator vs. other thrombolytic agents. It makes no more sense to withhold thrombolytic therapy in patients older than age 75 years than it would to withhold this life-saving treatment in other major demographic groups, such as women and African Americans.
Based on high-quality evidence from numerous prospective RCTs, thrombolytic therapy is clearly beneficial in carefully selected elderly patients with acute ST-elevation MI presenting within 6 hours of symptom onset. Although older age is a marker for increased risk of hemorrhagic stroke, the absolute risk is small and age is only one of several risk factors for stroke.
Therefore, concerns about the risk of stroke and major bleeding in elderly patients are unfounded, and these considerations should not preclude the use of thrombolytic treatment in the very elderly. Considering the totality of evidence currently available regarding the use of thrombolytic therapy in patients aged 75 years or older with ST-elevation MI, the American College of Cardiology/American Association guidelines a class IIa indication to such treatment, indicating that the weight of evidence/opinion is in favor of its usefulness and efficacy. It is my view that this recommendation is fully justified and appropriate.
Source...