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Department of Research, St Mary Mercy Hospital, Livonia, MichDepartment of Internal Medicine, College of Osteopathic Medicine, Michigan State University, East Lansing, Mich
Department of Research, St Mary Mercy Hospital, Livonia, MichDepartment of Internal Medicine, College of Osteopathic Medicine, Michigan State University, East Lansing, Mich
Intracranial hemorrhage is one of the dreaded complications of thrombolytic therapy for acute pulmonary embolism. We identified patients with pulmonary embolism who may be at relatively high risk of intracerebral hemorrhage from those selected for thrombolytic therapy by their physicians and presumably thought to be of reasonable risk.
Methods
The number of patients discharged from short-stay hospitals in the United States from 1998 to 2008 with pulmonary embolism who received thrombolytic therapy and the proportion with intracerebral hemorrhage were determined from the Nationwide Inpatient Sample, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality.
Results
From 1998 to 2008, 2,237,600 patients were discharged with a diagnosis of pulmonary embolism. Among patients who received thrombolytic therapy for pulmonary embolism, the prevalence of intracerebral hemorrhage was 430 of 49,500 (0.9%). The prevalence increased linearly with age more than 10 years. Intracerebral hemorrhage was less frequent in those with a primary diagnosis of pulmonary embolism (250/39,300 [0.6%]) than in those with a secondary diagnosis (180/10,300 [1.7%], P<.0001). The prevalence of intracerebral hemorrhage was lower in patients aged 65 years or less with no kidney disease (90/16,900 [0.5%]) than in patients aged more than 65 years or with kidney disease (290/20,900 [1.4%], P<.0001). The prevalence remained lower in those with a primary diagnosis (90/23,000 [0.4%] than in those with a secondary diagnosis (50/5700 [0.9%], P<.0001).
Conclusion
The cause of intracerebral hemorrhage in patients with pulmonary embolism who receive thrombolytic therapy seems to be multifactorial and related to comorbidity and age.
Intracranial hemorrhage is a dreaded complication of thrombolytic therapy for acute pulmonary embolism. Fear of intracranial hemorrhage is one of the reasons that thrombolytic therapy is used sparingly, and patients are selected with great caution and stringent indications.
Intracerebral hemorrhage associated with thrombolytic therapy in pulmonary embolism is age related.
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Prevalence of intracerebral hemorrhage is lower in those aged 65 years or less with no renal disease.
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Prevalence of intracerebral hemorrhage with thrombolytic therapy is higher in those with a secondary diagnosis of pulmonary embolism than in those with a primary diagnosis.
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Intracerebral hemorrhage with thrombolytic therapy is multifactorial and related to comorbidity and age.
The reported prevalence of intracranial hemorrhage, based on pooled data, registry, or hospital experience, ranged from 1% to 3%.
Although the number of patients who received thrombolytic therapy in these reports was sufficient to give useful information, the number of patients evaluated was a small fraction of patients in the database of the Nationwide Inpatient Sample.
The large number of patients who received thrombolytic therapy for pulmonary embolism in the Nationwide Inpatient Sample permitted an assessment of those who may be at high or low risk of intracranial hemorrhage among those already selected for treatment.
Materials and Methods
The number of patients discharged from short-stay hospitals throughout the United States from 1998 to 2008 with pulmonary embolism who received thrombolytic therapy and the proportion with intracerebral hemorrhage were determined from the Nationwide Inpatient Sample, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality.
The Nationwide Inpatient Sample is designed to approximate a 20% sample of US nonfederal, short-term hospitals as defined by the American Hospital Association and is stratified according to geographic region, ownership, location, teaching status, and bed size.
From 1998 to 2008, the Nationwide Inpatient Sample contained all discharge data from 984 to 1056 hospitals located in 22 to 42 states. In 2008, this sample comprised approximately 90% of all hospital discharges in the United States.
Weights are provided to calculate national estimates. The Nationwide Inpatient Sample is drawn from those states participating in the Healthcare Cost and Utilization Project. The Nationwide Inpatient Sample contains uniform inpatient data collected from existing hospital discharge databases maintained by state agencies, hospital associations, and other private data organizations.
The International Classification of Diseases, 9th Edition, Clinical Modification (ICD-9-CM) codes used for identification of patients in this investigation are shown in Table 1.
Table 1International Classification of Diseases, 9th Edition, Clinical Modification Codes Used
Patients with a first listed diagnostic code for pulmonary embolism were considered to have a primary diagnosis and assumed to have been admitted to the hospital because of pulmonary embolism.
Secondary Diagnosis of Pulmonary Embolism
Patients with a second or higher listed diagnostic code for pulmonary embolism were considered to have a secondary diagnosis and assumed to have been admitted to the hospital for reasons other than pulmonary embolism.
Unstable Definition
Unstable patients with pulmonary embolism were defined as those having a listed code for shock or on ventilator dependence.
Risk Factors for Bleeding
We assessed whether some of the clinical characteristics composing the Hypertension Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (>65 years), Drugs/alcohol concomitantly (HAS-BLED) bleeding risk score
could be used to identify patients at high risk of intracerebral hemorrhage from thrombolytic therapy. The HAS-BLED score was developed for assessing risk of major bleeding in patients taking oral anticoagulants with atrial fibrillation.
Characteristics in the HAS-BLED score that we could assess from ICD-9-CM discharge codes (Table 1) were hypertension, abnormal renal function (kidney disease), abnormal liver function (liver disease), stroke (ischemic), bleeding history or predisposition (blood loss anemia or coagulation defect), drug abuse, or alcoholism. Age also was assessed from the database.
Statistical Methods
Linear regression analyses using InStat version 3.0 (Graph Pad Software, San Diego, Calif) were used to calculate the slopes of linear segments in the curves describing the data for patients aged more than 10 years. Differences in prevalence of intracranial hemorrhage were assessed by chi-square using Graph Pad Software (San Diego, Calif). Age was presented as mean ± standard deviation, and comparisons were made using Student t test. Relative risk and 95% confidence intervals (CIs) were calculated using calculator for CIs of relative risk (www.sign.ac.uk/methodology/risk.xls). For values less than 500, we rounded off to the nearest 10. For values greater than 500, we rounded off to the nearest 100. In some instances, because of rounding off, the totals may have differed by 100. Proportions, relative risks, and probabilities were not affected.
Results
All Patients with Pulmonary Embolism
From 1998 to 2008, 2,237,600 patients were discharged from short-stay hospitals is in the United States with a diagnosis of pulmonary embolism. In Table 2, demographic characteristics are listed according to whether the diagnosis of pulmonary embolism was a primary or secondary diagnosis, whether the patients were stable or unstable, and whether they received thrombolytic therapy. The prevalence of intracerebral hemorrhage was the same in men (200/23,500 [0.9%]) and women (230/26,000 [0.9%]). The prevalence of intracerebral hemorrhage was higher in whites than blacks (260/28,100 [0.9%]) vs 20/5500 [0.4%], P<.0001) (relative risk 2.5, 95% CI, 1.6-4.0).
Table 2Age, Gender, Race According to Primary or Secondary Diagnosis, Stable or Unstable, and Thrombolytic Agents
Thrombolytic therapy was administered to 49,500 of 2,237,600 patients (2.2%) hospitalized with pulmonary embolism. Intracerebral hemorrhage occurred in 430 of 49,500 patients (0.9%) (95% CI, 0.79-0.95) (Table 3, Figure 1) . The incidence of intracerebral hemorrhage with thrombolytic therapy from 1998 to 2008 did not change.
Table 3Intracerebral Hemorrhage in All Patients Who Received Thrombolytic Therapy
Figure 1Proportion of patients with pulmonary embolism who received thrombolytic therapy and had intracerebral hemorrhage according to whether stable or unstable, whether diagnosis of pulmonary embolism was primary or secondary, and whether aged 65 years or less with no kidney disease. Prevalence of intracerebral hemorrhage in patients aged 65 years or less with no kidney disease was lower in each category (P<.0001) except unstable (P=.03). PE=pulmonary embolism.
The proportion of patients aged more than 10 years with pulmonary embolism who received thrombolytic therapy decreased linearly with age (Figure 2) . The proportion aged more than 10 years who had an intracerebral hemorrhage increased linearly with age (Figure 3) .
Figure 2Proportion of patients with a pulmonary embolism who received thrombolytic therapy in relation to age. For patients aged more than 10 years, r=−0.9805, P<.0001, slope=−0.4107/decade of age. PE=pulmonary embolism.
Figure 3Proportion of patients with pulmonary embolism who received thrombolytic therapy and had an intracerebral hemorrhage in relation to age. For patients aged more than 10 years, r=−0.9572, P=.0002, slope=0.1964/decade of age. PE=pulmonary embolism.
Among unstable patients with pulmonary embolism, 21,600 of 74,400 (29.0%) received thrombolytic therapy. Intracerebral hemorrhage occurred in 150 of 21,600 patients (0.7%) (95% CI, 0.58-0.80) (Table 3, Figure 1). In those who were stable, 27,900 of 2,163,200 (1.3%) received thrombolytic therapy. Intracerebral hemorrhage occurred in 280 of 27,900 patients (1.0%) (95% CI, 0.88-1.12) (P=.0003).
Primary Diagnosis of Pulmonary Embolism Compared with Secondary Diagnosis
Among patients with a primary diagnosis of pulmonary embolism, 39,300 of 1,320,200 (3.0%) received thrombolytic therapy. Intracerebral hemorrhage occurred in 250 of 39,300 (0.6%) (95% CI, 0.56-0.72) (Table 3, Figure 1). In those with a secondary diagnosis of pulmonary embolism, 10,300 of 917,400 (1.1%) received thrombolytic therapy. Among these, 180 of 10,300 (1.7%) (95% CI, 1.50-2.00) had an intracerebral hemorrhage (Table 3, Figure 1). The prevalence of intracerebral hemorrhage in those with a secondary diagnosis of pulmonary embolism was higher than in those with a primary diagnosis (P<.0001; relative risk, 0.36; 95% CI, 0.30-0.44).
Bleeding Risks and Intracerebral Hemorrhage
Among the 49,500 patients who received thrombolytic therapy, if all of the factors in the HAS-BLED score that we could assess from ICD-9-CM discharge codes were eliminated (hypertension, kidney disease, liver disease, stroke [ischemic], blood loss anemia or coagulation defect, age>65 years, drug abuse, or alcoholism), 16,900 (34.0%) at low risk of bleeding remained. Intracerebral hemorrhage occurred in 90 of 16,900 patients (0.5%). If only those with kidney disease or aged more than 65 years were eliminated, then 28,600 patients (58%) remained. Intracerebral hemorrhage occurred in 140 of 28,600 patients (0.5%) (95% CI, 0.41-0.57) (Table 4). Patients aged 65 years or less with no kidney disease had a lower risk of intracerebral hemorrhage than those aged more than 65 years or with kidney disease, 90 of 16,900 (0.5%) compared with 290 of 20,900 (1.4%) (P<.0001) (relative risk, 0.4; 95% CI, 0.30-0.49).
Table 4Intracerebral Hemorrhage in Patients Aged 65 Years or Less and with No Kidney Disease Who Received Thrombolytic Therapy
After elimination of those aged more than 65 years or with kidney disease, in patients with a primary diagnosis of pulmonary embolism the prevalence of intracerebral hemorrhage was 90 of 23,000 (0.4%) (95% CI, 0.31-0.47), and in patients with secondary diagnosis of pulmonary embolism the prevalence of intracerebral hemorrhage was 50 of 5700 (0.9%) (95% CI, 0.64-1.12) (Table 4, Figure 1). By comparing those with a primary diagnosis of pulmonary embolism aged 65 years or less with no kidney disease with all patients with a primary diagnosis of pulmonary embolism, the relative risk of intracerebral hemorrhage was 0.7 (95% CI, 0.60-0.85). A greater reduction of risk was shown in those with a secondary diagnosis of pulmonary embolism (relative risk, 0.6; 95% CI, 0.47-0.78).
Discussion
The prevalence of intracerebral hemorrhage in patients with pulmonary embolism who received thrombolytic therapy was 0.9%. The prevalence of intracerebral hemorrhage increased with age and was lower in those with a primary diagnosis of pulmonary embolism (0.6%) than in those with a secondary diagnosis (1.7%). The prevalence of intracerebral hemorrhage in those aged 65 years or less with no kidney disease was 0.5% compared with 1.4% in those aged more than 65 years or with kidney disease. Among patients aged 65 years or less with no kidney disease, the prevalence of intracerebral hemorrhage remained higher in those with a secondary diagnosis of pulmonary embolism than in those with a primary diagnosis.
The cause of intracerebral hemorrhage in patients with pulmonary embolism who receive thrombolytic therapy is multifactorial and related to comorbidity and age. The prevalence of intracerebral hemorrhage among patients with a secondary diagnosis of pulmonary embolism (1.7%) was approximately twice the prevalence of patients with a primary diagnosis (0.9%). This suggests that the illnesses for which patients were hospitalized affected the prevalence of intracerebral hemorrhage caused by thrombolytic therapy. Palareti and Cosmi,
in a review of the bleeding risks of anticoagulation, observed that comorbidities might represent a significant risk factor for bleeding during treatment. We identified age more than 65 years (with its unidentified comorbidities and bleeding risks) and kidney disease as 2 important risk factors for intracerebral hemorrhage. Patients aged 65 years or less with no kidney disease had the same prevalence of intracerebral hemorrhage as patients aged 65 years or less with no kidney disease, hypertension, abnormal liver function, ischemic stroke, bleeding history or predisposition, alcoholism, or drug abuse. Use of only these 2 risk factors (age>65 years or renal disease) was simpler and eliminated fewer patients who might have been considered to be at a high risk of bleeding.
We recognize that the patients included in this study are already a highly selected population, presumably deemed to be at an acceptably low risk of bleeding by the physicians who elected to administer the thrombolytic therapy. Although on average we observed a 0.9% prevalence of intracranial bleeding, our data identify those at higher or lower risk of intracerebral hemorrhage among this selected group. Kanter et al
reported intracerebral bleeding in 1.2%, based on pooled data of 5 trials in which patients were required to have none of several specified risk factors for bleeding. Fiumara et al
reported a 1.0% prevalence of intracranial hemorrhage based on retrospective data from a single hospital in which selection for treatment was based on clinical judgment. Patients in the International Cooperative Pulmonary Embolism Registry (ICOPER) who received thrombolytic therapy also were selected on the basis of clinical judgment, and they reported a prevalence of intracranial hemorrhage of 3.0%.
Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry.
described stable patients with pulmonary hypertension or right ventricular dysfunction who were treated with thrombolytic agents. Data from a registry suggested an improved clinical course compared with heparin alone,
Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry.
Among patients in the registry, intracerebral hemorrhage occurred in 2 of 169 (1.2%), but in the randomized trial there was no intracerebral bleeding among 118 patients who received thrombolytic therapy.
Our data, among 27,900 stable patients who received thrombolytic therapy, showed an intracerebral hemorrhage in 1.0%.
To our knowledge, previous investigators did not stratify the risk of thrombolytic-induced intracerebral hemorrhage according to whether pulmonary embolism was a primary or secondary diagnosis. Also, previous investigators did not attempt to estimate the risk of thrombolytic-induced intracerebral hemorrhage in relation to comorbid conditions or age. Age, however, has been shown to be a risk factor for major bleeding in patients who received thrombolytic therapy for pulmonary embolism.
A 4% increase in risk of major bleeding with thrombolytic therapy was shown for each incremental year of age in a population in whom those with standard risk factors for bleeding were excluded.
The prevalence of intracerebral hemorrhage was more than twice as high in whites compared with blacks. We are not aware of other investigations that described the prevalence of intracerebral bleeding according to race.
Strengths of this investigation include the huge number of patients in a population that included all ages, races, and both genders. The large number of patients made it possible to stratify according to primary and secondary diagnoses of pulmonary embolism, stable and unstable. Although there may be imperfect sensitivity of ICD-9-CM codes, relative risks of intracerebral hemorrhage, comparing various categories of treated patients, are likely to be correct. Weaknesses include an inability to identify the regimen of thrombolytic therapy. In addition, we could not identify the comorbid conditions that induced a higher prevalence of thrombolytic-associated intracerebral hemorrhage in those with a secondary diagnosis of pulmonary embolism.
Validation of ICD-9-CM Codes
The specificity of ICD-9-CM coding is high. Thus, the majority of patients whose codes indicated that they received thrombolytic therapy actually did receive the therapy. The frequencies reported, however, are underreported because of the imperfect sensitivity of coding for capturing treatment or diagnostic procedures.
Even so, the proportion of patients with pulmonary embolism that we report who received thrombolytic therapy (2.2%) was comparable to the proportion in the EMPORER registry (1.8%)
Clinical characteristics, management, and outcomes of patients diagnosed with acute pulmonary embolism in the emergency department initial report of EMPEROR (Multicenter Emergency Medicine Pulmonary Embolism in the Real World Registry).
It is likely that the sensitivity of coding for thrombolytic therapy and ventilatory support was high because reimbursement is directly linked to the extent of coding. This has been the case since the early 1980s, when the Health Care Financing Administration introduced Diagnosis-Related Groups as a mechanism for reimbursing hospitals that provide care to Medicare recipients.
Review and reabstraction of a sample of Medicare hospitalizations showed that 92% of codable cases for pulmonary embolism were on the abstract.
A 0.4% prevalence of pulmonary embolism in hospitalized whites and African Americans aged more than 20 years throughout the United States, based on use of ICD-9-CM codes,
Pulmonary thromboembolism in Asian/Pacific Islanders in the United States: analysis of data from the National Hospital Discharge Survey and the United States Bureau of the Census.
was remarkably close to the incidences of pulmonary embolism in a university hospital (0.4%), a non-university tertiary care center (excluding estimates of undiagnosed pulmonary embolism in patients who died, 0.4%) and a community/teaching hospital (0.3%), based on multiple data sources including radiographic reports and autopsies.
In regard to the robustness of the code for intracerebral hemorrhage, it would be extraordinary to imagine that some patients were coded as having this complication when they did not. Some patients, however, may have had an intracerebral hemorrhage that was not coded. Therefore, our data may show a lower prevalence of intracerebral hemorrhage than actually occurred.
In regard to coding for shock and ventilatory support that we used for the identification of unstable patients, we found that 3.3% were unstable, which was similar to the 4.2% reported to be unstable in the ICOPER.
Even so, we focused on relative changes rather than absolute values and assumed that the sensitivity of coding was the same in patients with a primary diagnosis of pulmonary embolism and those with a secondary diagnosis.
We do not have data on the validity of a first listed diagnosis as being indicative of a primary diagnosis and second or later listed diagnosis as a secondary diagnosis. Patients with a first listed diagnosis were assumed to have been hospitalized because of pulmonary embolism, and patients with a second or higher listed diagnostic code for pulmonary embolism were assumed to have been hospitalized for reasons other than pulmonary embolism. Our data support this assumption, based on higher rates of intracerebral hemorrhage among those with a secondary diagnosis, who are more likely to have comorbid conditions that could contribute to the risk of intracerebral hemorrhage.
Conclusions
Intracerebral hemorrhage associated with thrombolytic therapy in patients with pulmonary embolism was age related, and the prevalence was higher in those with a secondary diagnosis of pulmonary embolism than in those with a primary diagnosis. This suggests that comorbid conditions contribute to its prevalence. The prevalence of intracerebral hemorrhage was lower in those aged 65 years or less with no renal disease. However, the prevalence remained higher in those with a secondary diagnosis than in those with a primary diagnosis of pulmonary embolism, even after exclusion of patients aged more than 65 years or with renal disease. The cause of intracerebral hemorrhage in patients with pulmonary embolism who receive thrombolytic therapy seems to be multifactorial and related to comorbidity and age.
References
Dalen J.E.
Alpert J.S.
Hirsh J.
Thrombolytic therapy for pulmonary embolism: is it effective?.
Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry.
Clinical characteristics, management, and outcomes of patients diagnosed with acute pulmonary embolism in the emergency department initial report of EMPEROR (Multicenter Emergency Medicine Pulmonary Embolism in the Real World Registry).
Pulmonary thromboembolism in Asian/Pacific Islanders in the United States: analysis of data from the National Hospital Discharge Survey and the United States Bureau of the Census.
Acute glomerulonephritis, nephrotic syndrome, chronic glomerulonephritis, nephritis, and nephropathy not specified as acute or chronic, acute renal failure, chronic kidney disease, renal failure unspecified, disorders resulting from impaired renal function.
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