CLINICAL RESEARCH STUDY

Thrombolytic Therapy in Unstable Patients with Acute Pulmonary Embolism: Saves Lives but Underused Paul D. Stein, MD,a,b Fadi Matta, MDa,b a

Department of Research, St Mary Mercy Hospital, Livonia, Michigan; bDepartment of Medicine, Michigan State University College of Osteopathic Medicine, East Lansing.

ABSTRACT BACKGROUND: Data are sparse and inconsistent regarding whether thrombolytic therapy reduces case fatality rate in unstable patients with acute pulmonary embolism. We tested the hypothesis that thrombolytic therapy reduces case fatality rate in such patients. METHODS: In-hospital all-cause case fatality rate according to treatment was determined in unstable patients with pulmonary embolism who were discharged from short-stay hospitals throughout the United States from 1999 to 2008 by using data from the Nationwide Inpatient Sample. Unstable patients were in shock or ventilator dependent. RESULTS: Among unstable patients with pulmonary embolism, 21,390 of 72,230 (30%) received thrombolytic therapy. In-hospital all-cause case fatality rate in unstable patients with thrombolytic therapy was 3105 of 21,390 (15%) versus 23,820 of 50,840 (47%) without thrombolytic therapy (P ⬍ .0001). All-cause case fatality rate in unstable patients with thrombolytic therapy plus a vena cava filter was 505 of 6630 (7.6%) versus 4260 of 12,850 (33%) with a filter alone (P ⬍ .0001). Case fatality rate attributable to pulmonary embolism in unstable patients was 820 of 9810 (8.4%) with thrombolytic therapy versus 1080 of 2600 (42%) with no thrombolytic therapy (P ⬍ .0001). Case fatality rate attributable to pulmonary embolism in unstable patients with thrombolytic therapy plus vena cava filter was 70 of 2590 (2.7%) versus 160 of 600 (27%) with a filter alone (P ⬍ .0001). CONCLUSION: In-hospital all-cause case fatality rate and case fatality rate attributable to pulmonary embolism in unstable patients was lower in those who received thrombolytic therapy. Thrombolytic therapy resulted in a lower case fatality rate than using vena cava filters alone, and the combination resulted in an even lower case fatality rate. Thrombolytic therapy in combination with a vena cava filter in unstable patients with acute pulmonary embolism seems indicated. © 2012 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2012) 125, 465-470 KEYWORDS: Pulmonary embolism; Thrombolytic therapy; Venous thromboembolism SEE RELATED EDITORIAL AND ARTICLES pp. 429, 471, and 478

Since the first clinical report of the use of a thrombolytic agent (streptokinase) in patients with pulmonary embolism by Browse and James in 1964,1 several randomized controlled trials, beginning with the Urokinase Pulmonary Embolism Trial,2 showed more rapid lysis of pulmonary thromFunding: None. Conflict of Interest: None. Authorship: All authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Paul D. Stein, MD, St Mary Mercy Hospital, 36475 Five Mile Road, Livonia, MI 48154. E-mail address: [email protected]

0002-9343/$ -see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2011.10.015

boemboli with thrombolytic agents than with anticoagulants alone.3-8 Among symptomatic patients with pulmonary embolism who were not in shock, randomized controlled trials2,5-10 showed that case fatality rate was comparable in those treated with thrombolytic agents and those treated with anticoagulants alone. A meta-analysis of patients not in shock showed no benefit of thrombolytic agents compared with anticoagulants in terms of recurrent pulmonary embolism or death.11 Thrombolytic therapy would seem appropriate in patients in shock;12 however, data are sparse and inconsistent. Among patients in shock in the Urokinase Pulmonary Em-

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bolism Trial, 2-week case fatality rate among those treated Identification of Pulmonary Embolism with urokinase was 2 of 2 (100%) versus 1 of 1 (100%) in The International Classification of Diseases, 9th Edition, those treated with anticoagulants.2 In a trial of patients with Clinical Modification (ICD-9-CM) codes used for identifimassive pulmonary embolism in shock, case fatality rate cation of patients with pulmonary embolism were 415.1, was 0 of 4 (0%) in patients randomized to streptokinase 634.6, 635.6, 636.6, 637.6, 638.6, and 673.2. and 4 of 4 (100%) among patients randomized to heparin alone Primary Diagnosis of (P ⫽ .02).13 Among hypotensive Pulmonary Embolism CLINICAL SIGNIFICANCE patients with pulmonary emboPatients with a first listed diagnoslism in the International Coopera● All-cause in-hospital case fatality rate tic code for pulmonary embolism tive Pulmonary Embolism Regiswas reduced from 47% to 15% with were considered to have a primary try (ICOPER), 90-day case fatality thrombolytic therapy in unstable padiagnosis, and we assumed they rate was similar in 33 patients who tients with pulmonary embolism. were admitted to the hospital bereceived thrombolytic therapy and cause of pulmonary embolism. ● Death attributable to pulmonary emboin 73 patients who did not (46% vs 14 55%). Meta-analysis of 5 trials lism was reduced from 42% to 8% with Identification of Vena that included patients with unstathrombolytic therapy in unstable paCava Filter Insertion ble pulmonary embolism and patients with pulmonary embolism. The ICD-9-CM code used for intients who were not unstable ● Thrombolytic therapy resulted in a lower sertion of a vena cava filter was showed a lower end point of death case fatality rate than using vena cava 38.7, “Interruption of the vena or recurrent pulmonary embolism cava, insertion of implant or sieve filters alone. in patients treated with thromboin vena cava, ligation of vena cava lytic agents (9.4% vs 19.0%).11 ● The combination of thrombolytic ther(inferior, superior), plication of There are no definitive trials apy and vena cava filters resulted in the vena cava.” Since 1979, this code that prove the value of thrombolowest case fatality rate in unstable paapplies almost entirely to vena lytic therapy in unstable patients tients with pulmonary embolism. cava filters. From 1979 to 1985, with pulmonary embolism. It is the use of surgical caval interrupextremely remote that a randomtion decreased to virtually zero.16 ized controlled trial will be performed in the future. We therefore analyzed the database of Thrombolytic Therapy the Nationwide Inpatient Sample to test the hypothesis that Thrombolytic therapy was identified as ICD-9-CM procethrombolytic therapy reduces case fatality rate in unstable dure code 99.10. patients with acute pulmonary embolism.

MATERIALS AND METHODS Unstable patients with acute pulmonary embolism discharged from short-stay hospitals throughout the United States from 1999 to 2008 and their in-hospital mortality according to the use of thrombolytic therapy were identified from the Nationwide Inpatient Sample, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality.15 The Nationwide Inpatient Sample contains data from 5 to 8 million hospital stays from approximately 1000 hospitals. It 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.3 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 stay data collected from existing hospital discharge databases maintained by state agencies, hospital associations, and other private data organizations.15

Embolectomy Pulmonary embolectomy was identified as ICD-9-CM procedure code 38.05. Catheter embolectomy was presumed to be ICD-9-CM procedure code 39.79, endoluminal repair, other.

Definition of Unstable Unstable was defined as having a listed code for shock (ICD-9-CM code 785.5) or ventilator dependence (ICD9-CM code V46.1).

Comorbid Conditions The conditions included in the Charlson comorbidity index17 and the ICD-9-CM codes that we used to identify these conditions are shown in Table 1. This method of classifying comorbidity provides a simple, readily applicable, and valid method of estimating risk of death from comorbid disease.17

Statistical Methods Differences in case fatality rates were assessed by chisquare and relative risk, and 95% confidence intervals (CIs)

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Table 1 Comorbid Conditions in Unstable Patients and International Classification of Diseases, 9th Edition, Clinical Modification Codes Used Unstable

Condition

ICD-9-CM Codes

Acute myocardial infarction Heart failure Peripheral vascular disease Cerebrovascular disease Dementia Chronic obstructive pulmonary disease Rheumatologic disease

410 428 440.2, 443.9 430-438 290 490-496 710.0, 710.1, 710.4, 714.0, 714.1, 714.2, 714.8 531-534 570, 571 250.0-250.3 342.0-342.9 344.1 580-586, 588 250.4-250.6 140-195, 200-208 196-199 042

Ulcer disease Acute or chronic liver disease Diabetes mellitus Hemiplegia and hemiparesis Paraplegia Moderate or severe renal disease Diabetes with chronic complications Any neoplasms, leukemia, lymphoma Metastatic cancer HIV and AIDS

Thrombolytics Therapy (21,390) n (%)

No Thrombolytics Therapy (50,840) n (%)

P Value

1010 3170 325 830 50 3650 170

(4.7) (15) (1.5) (3.9) (0.2) (17) (0.8)

7420 13,520 920 3990 255 11,400 540

(15) (27) (1.8) (7.8) (0.5) (22) (1.1)

⬍.0001 ⬍.0001 .006 ⬍.0001 ⬍.0001 ⬍.0001 .001

265 510 3330 140 0 325 5 80 65 5

(1.2) (2.4) (16) (0.7) (0) (34) (0.5) (8.4) (6.8) (0.5)

1200 3030 5680 400 195 21,090 870 7910 4900 500

(2.4) (6.0) (11) (0.8) (0.4) (42) (1.7) (16) (9.6) (1.0)

⬍.0001 ⬍.0001 ⬍.0001 NS .01 ⬍.0001 NS ⬍.0001 ⬍.0001 ⬍.0001

ICD-9-CM ⫽ International Classification of Diseases, 9th Edition, Clinical Modification; HIV ⫽ human immunodeficiency virus; AIDS ⫽ acquired immune deficiency syndrome; NS ⫽ not significant.

RESULTS From 1999 to 2008, 2,110,320 patients were discharged from short-stay hospitals in the United States with a diagnosis of pulmonary embolism. Among these, 72,230 (3.4%) were unstable (in shock or ventilator dependent). Among unstable patients, 21,390 (30%) received thrombolytic therapy and 50,840 (70%) did not. Associated comorbid conditions were more often present in those who did not receive thrombolytic therapy than in those who did (Table 1). The proportion of unstable patients who received thrombolytic therapy decreased linearly from 1999 to 2008 from 40% to 23% (Figure 1). Among unstable patients who did not receive thrombolytic therapy, only 1.2% underwent open pulmonary embolectomy and 0.3% underwent catheter-tip embolectomy. Among unstable patients who received thrombolytic therapy, all-cause in-hospital case fatality rate was 3105 of

21,390 (15%) compared with 23,820 of 50,840 (47%) in unstable patients who did not receive thrombolytic therapy (P ⬍ .0001) (relative risk 0.31; 95% CI, 0.30-0.32) (Figure 2). Patients who received thrombolytic therapy were younger than those who did not receive thrombolytic therapy, 58 ⫾ 17 years versus 65 ⫾ 17 years, respectively (P ⬍ .0001). Age-matched patients in every decade of age more than 10 years had a lower all-cause case fatality rate with

45

Unstable Patients who Received Thrombolytic Therapy (%)

were calculated using GraphPad software (GraphPad Software Inc, San Diego, Calif). Linear regression analyses were used to calculate slopes of the curves using GraphPad software. Age and length of stay were presented as mean ⫾ standard deviation, and comparisons were made using the Student t test. Case fatality rate was defined as the proportion of patients with pulmonary embolism who died in-hospital (%). Death was attributed to pulmonary embolism among patients with a primary (first-listed) diagnosis of pulmonary embolism who had none of the comorbid conditions listed in the Charlson Index.17

30

15

0 1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

Year

Figure 1 Proportion of unstable patients with pulmonary embolism who received thrombolytic therapy. The proportion decreased linearly from 1999 to 2008 (r ⫽ ⫺0.9797, slope ⫺1.1998 %/year, P ⬍ .0001).

In-hospital All-cause Case Fatality Rate In Unstable Patients (%)

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47

25

15

n= 21,390

n= 50,840

Thrombolytic Therapy

No Thrombolytic Therapy

0

Figure 2 In-hospital all-cause case fatality rate in unstable patients with pulmonary embolism who received thrombolytic therapy and in those who did not. The number (n) in both groups is shown within the bar. Difference of mortality, P ⬍ .0001.

thrombolytic therapy. The proportion of women among treated and untreated patients was similar, 53% versus 51%, respectively (not significant). Average length of stay in unstable patients who received thrombolytic therapy was 9 ⫾ 4 days. All-cause case fatality rate in unstable patients who received thrombolytic therapy but did not receive a vena cava filter was 2600 of 14,760 (18%) compared with 19,560 of 38,000 (51%) in patients who received neither thrombolytic therapy nor a vena cava filter (P ⬍ .0001) (relative risk 0.29;

42

45 PE Attributable Case Fatality Rate In Unstable Patients (%)

95% CI, 0.28-0.31); age was 57 ⫾ 17 years versus 64 ⫾ 17 years, respectively (P ⬍ .0001). Age-matched patients in every decade of age more than 10 years had lower all-cause case fatality rate with thrombolytic therapy. All-cause case fatality rate in unstable patients who received thrombolytic therapy plus a vena cava filter was 505 of 6630 (7.6%) compared with 4260 of 12,850 (33%) in patients who did not receive thrombolytic therapy but received a vena cava filter (P ⬍ .0001) (relative risk 0.25; 95% CI, 0.23-0.27); age was 59 ⫾ 16 years versus 66 ⫾ 15 years, respectively (P ⬍ .0001). Age-matched patients in every decade of age more than 20 years had lower all-cause case fatality rate with thrombolytic therapy. Data were insufficient to assess younger patients. Case fatality rate attributable to pulmonary embolism among unstable patients was 820 of 9810 (8.4%) with thrombolytic therapy compared with 1080 of 2600 (42%) among patients who did not receive thrombolytic therapy (P ⬍ .0001) (relative risk 0.20; 95% CI, 0.19-0.22) (Figure 3). Patients who received thrombolytic therapy were younger than those who did not receive thrombolytic therapy (54 ⫾ 17 years vs 64 ⫾ 16 years, respectively; P ⬍ .0001). Age-matched patients who received thrombolytic therapy in every decade of age more than 20 years showed a lower case fatality rate attributable to pulmonary embolism. Data were insufficient in younger patients. Case fatality rate attributable to pulmonary embolism among unstable patients who received thrombolytic therapy plus a vena cava filter was 70 of 2590 (2.7%) compared with 160 of 600 (27%) in those who received only a vena cava filter (P ⬍ .0001) (relative risk 0.10; 95% CI, 0.08-0.13).

27

30

15

8.4 2.7 0

n= 9,810 n= 2,600 Thrombolytic No Therapy Thrombolytic Therapy

n= 2,590

n= 600

Thrombolytic No Therapy Thrombolytic + VC Filter Therapy, VC Filter Used

Figure 3 In-hospital death attributable to pulmonary embolism in unstable patients with pulmonary embolism. All unstable patients (left). Unstable patients who received a vena cava filter (right). The number (n) in each group is shown within the bar. Differences of case fatality rate, P ⬍ .0001. PE ⫽ pulmonary embolism; VC ⫽ vena cava.

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Patients who received thrombolytic therapy were younger than those who did not receive thrombolytic therapy (55 ⫾ 18 years vs 64 ⫾ 13 years, respectively; P ⬍ .0001). Data were sufficient for matching patients aged more than 40 years according to decades of age. In each decade of age, case fatality rate was lower with thrombolytic therapy. Among unstable patients with a primary diagnosis of pulmonary embolism who received thrombolytic therapy, 22% died on the day of admission, 25% died 1 day after admission, and 14% died 2 days after admission. Among those who did not receive thrombolytic therapy, 16% died on the day of admission, 23% died 1 day after admission, and 11% died 2 days after admission.

DISCUSSION Thrombolytic therapy in unstable patients was associated with a lower in-hospital all-cause case fatality rate and fewer deaths attributable to pulmonary embolism. Despite these reductions in case fatality rate, thrombolytic therapy was administered to only 30% of unstable patients, and the use of thrombolytic therapy in unstable patients with pulmonary embolism decreased from 1999 to 2008. Pulmonary embolectomy cannot explain the reduced use of thrombolytic therapy. Only 1.2% of unstable patients received open pulmonary embolectomy without thrombolytic therapy, and 0.3% received catheter-tip embolectomy without thrombolytic therapy. Catheter-tip embolectomy is used in combination with local or systemic thrombolytic therapy in the majority of patients.18 Use of vena cava filters in unstable patients was associated with a lower case fatality rate.19 Irrespective of the use of vena cava filters, case fatality rate was lower in those who received thrombolytic therapy. Case fatality rate was lowest in those who received thrombolytic therapy plus a vena cava filter. Only 16% of unstable patients with a primary diagnosis of pulmonary embolism died on the day of admission. Therefore, there was time to administer thrombolytic therapy to the majority of unstable patients who died. Among unstable patients who received vena cava filters, there clearly would have been time to administer thrombolytic therapy in addition to insertion of a filter. Unstable patients who received thrombolytic therapy were 7 years younger on average than those who did not receive thrombolytic therapy. This difference in age would not explain the large reduction in case fatality rate with thrombolytic therapy because only small increments of case fatality rate occur with increments of age 10 years or less.20 Age-matched unstable patients showed a lower case fatality rate with thrombolytic therapy. Although unstable patients who received thrombolytic therapy had fewer comorbid conditions than those who did not, this would not explain the difference in case fatality rate because unstable patients with a primary diagnosis of pulmonary embolism and none of the comorbid conditions listed in the Charlson index also showed a lower case fatality rate with thrombolytic therapy. Therefore, differ-

469 ences in comorbid conditions in this group were eliminated as a possible cause of the lower case fatality rate in unstable patients who received thrombolytic therapy. Strengths of this investigation are the large number of patients of both genders with a wide range of ages. A sufficiently large sample of patients was obtained to assess whether thrombolytic therapy reduces case fatality rate in unstable patients with pulmonary embolism. A study limitation is that the data are retrospective and based on ICD9-CM discharge codes. The sensitivity and specificity of ICD-9-CM discharge codes relevant to these data have been discussed.19 The robustness of the coding is supported by the similarity of our results to those of the ICOPER when comparing observations in which the ICOPER had a substantial number of patients.11 We showed that 3.4% of patients with pulmonary embolism were unstable versus 4.5% in the ICOPER (defining unstable as hypotensive). We showed that only 30% of unstable patients received thrombolytic therapy versus 31% in the ICOPER. Among unstable patients who did not receive thrombolytic therapy, we showed that only 1.2% underwent pulmonary embolectomy versus 1.9% in the ICOPER (not counting those who received both). We estimated that 0.3% were treated with catheter-tip embolectomy without thrombolytic therapy, but in the ICOPER, no patients were treated with catheter-tip embolectomy without thrombolytic therapy. Frailty of coding for thrombolytic therapy could not explain the lower case fatality rate we showed with the coding. If those who did not receive a procedure code for thrombolytic therapy did receive thrombolytic therapy, their case fatality rate should have been similar to the case fatality rate of those who received a procedure code for thrombolytic therapy. The American College of Chest Physicians EvidenceBased Clinical Practice Guidelines (8th edition) recommend thrombolytic therapy for patients with evidence of hemodynamic compromise unless there are major contraindications due to bleeding risk.21 The recommendation was based on evidence of accelerated lysis of thrombi with thrombolytic therapy and trends toward improved clinical outcome in subgroups of patients with hemodynamic compromise.21 The data from the present investigation directly show that thrombolytic therapy reduces case fatality rate in unstable patients with acute pulmonary embolism.

CONCLUSIONS All-cause case fatality rate and case fatality rate attributable to pulmonary embolism were lower in unstable patients with pulmonary embolism who received thrombolytic therapy than in those who did not receive thrombolytic therapy. Thrombolytic therapy was associated with a larger reduction of case fatality rate than using vena cava filters without thrombolytic therapy, and thrombolytic therapy was associated with an even lower case fatality rate when used in combination with vena cava filters. Therefore, vena cava filters should not be considered a substitute for thrombolytic

470 therapy in unstable patients with pulmonary embolism, but they are an important adjunct to therapy. Despite the marked reduction of case fatality rate with thrombolytic therapy in unstable patients, only 30% of unstable patients received it, and the proportion receiving thrombolytic therapy is diminishing. On the basis of these data, thrombolytic therapy in combination with a vena cava filter in unstable patients with acute pulmonary embolism seems indicated.

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