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Thrombolytics and Vena Cava Filters Decrease Mortality in Patients with Unstable Pulmonary Embolism
EDITORIAL
Thrombolytics and Vena Cava Filters Decrease Mortality in Patients with Unstable Pulmonary Embolism SEE RELATED ARTICLES pp. 465, 471, and 478.
Standard anticoagulant therapy is very effective in patients with pulmonary embolism who are hemodynamically stable. Hospital mortality is in the range of 5% or less.1 However, in patients with shock secondary to massive pulmonary embolism, mortality ranges from 30% to 50%.2 A small minority of patients with pulmonary embolism present in shock. In a series of 2392 patients with pulmonary embolism, Kucher et al3 reported that only 4.5% of 2392 patients with pulmonary embolism had a systolic pressure less than 90 mm Hg and a hospital mortality of 52%. Three articles in this issue of The American Journal of Medicine by Stein et al4 and Stein and Matta5,6 provide impressive evidence that thrombolytics and vena cava filters, especially when used together, have a dramatic impact on the case fatality of patients with pulmonary embolism who are unstable, defined as in shock or requiring ventilator support. These studies are based on a review of all patients (⬎2 million) with acute pulmonary embolism who were discharged from 1000 US acute care hospitals over a 10- or 11-year period from 1999 to 2008. In their first article, Stein et al4 focus on the use of vena cava filters. Before the introduction of anticoagulants, the only treatment to prevent recurrent venous thromboembolism was ligation of the femoral veins. This was first performed by Homans in 1934.2 Homans later advocated ligation of the inferior vena cava, which had significant morbidity and mortality. Vena cava clips that partially occluded the vena cava, but prevented the passage of major emboli, were introduced by Moretz et al in 1959.7 MobinUddin2 developed an umbrella-like filter that could be introduced transvenously, thereby avoiding laparotomy. Further designs of filters have made them smaller, retrievable, and able to be introduced at the bedside with ultrasound guidance.8 The use of filters in the treatment and prevention of venous thromboembolism has accelerated in the United States from 2000 in 1979 to 92,000 in 2006.8 The American Funding: None. Conflict of Interest: None. Authorship: The author is solely responsible for the content of this manuscript.
0002-9343/$ -see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2011.09.023
College of Chest Physicians’ guidelines for antithrombotic and thrombolytic therapy only recommend inferior vena cava filters for patients with venous thromboembolism who have a contraindication to anticoagulants.1 Many clinicians recommend vena cava filters in patients who are hemodynamically unstable to reduce the risk of early recurrent embolism, which could be fatal in these critically ill patients. The one randomized clinical trial9 of vena cava filters plus anticoagulants compared with anticoagulants alone demonstrated a decreased rate of recurrent pulmonary embolism in the first 8 days of anticoagulant treatment. However, there was no decrease in mortality. It should be noted that these patients were not at high risk, and none were hemodynamically unstable and not all had pulmonary embolism. Stein et al4 reported that the mortality of 2 million patients with pulmonary embolism who were stable was 7.9% compared with 37% in the 72,230 patients who were unstable. The mortality in 38,000 unstable patients treated with standard anticoagulant therapy alone was 51% compared with 33% in 12,850 who had vena cava filters in addition to anticoagulants.4 This represents an impressive 35% decrease in the case fatality rate when vena cava filters are combined with standard anticoagulant therapy! In a second article, Stein and Matta5 focus on thrombolytic therapy. Thrombolytic therapy has been available since the Urokinase Pulmonary Embolism Trial in 197310 reported more rapid resolution of pulmonary emboli with urokinase than with heparin. However, there was no significant difference in mortality. Multiple reports since then have again shown a more rapid resolution of pulmonary embolism with tissue plasminogen activator.11 However, no randomized trials have reported a decreased mortality with thrombolytics compared with heparin in patients with hemodynamically unstable pulmonary embolism.1,11 The American College of Chest Physicians’ guidelines recommend thrombolytics for patients with pulmonary embolism if there is evidence of hemodynamic compromise and no major contraindications to thrombolytic therapy. This a grade 1B recommendation.1
430 Stein and Matta5 report that 21,390 patients with unstable pulmonary embolism received thrombolytics in addition to anticoagulants, and their mortality was 14.5% compared to 47% in those not receiving thrombolytics. The risk reduction was 69%. The results in 6630 unstable patients who received vena cava filters and thrombolytics were even more impressive. They had a fatality rate of 7.6% compared with 52% in 38,000 patients who received neither (85% risk reduction). The 7.6% mortality in the unstable patients who received a filter and thrombolytics was approximately the same (7.9%) as in 2 million stable patients treated with conventional anticoagulants. Stein and Matta6 examined the impact of pulmonary embolectomy on the mortality of those with unstable pulmonary embolism. Pulmonary embolectomy was first performed by Trendelenburg in 1908.12 It was the only known therapy for pulmonary embolism until the introduction of venous ligation in 1934.2 In 4 series with a total of 167 patients with massive pulmonary embolism and shock who underwent embolectomy between 1968 and 1997, the mortality was 35%.12 Stein and Matta6 reported that 950 patients with unstable pulmonary embolism underwent embolectomy between 1999 and 2008. The mortality was 40%. However, in 520 patients who had a filter in addition to embolectomy, the mortality was 25%.6 The findings in these 3 reports are not the result of randomized clinical trials. Given the fact that less than 5% of patients with pulmonary embolism are hemodynamically unstable, it is not surprising that randomized trials of vena cava filters or thrombolytics or embolectomy in patients with unstable pulmonary embolism have not been reported. It is highly unlikely that randomized trials of therapy for patients with unstable pulmonary embolism will ever be reported. These dramatic findings in the more than 72,000 patients who were treated for unstable pulmonary embolism in US hospitals from 1999 to 2008 indicate to this clinician that thrombolytic therapy (in those without contraindications) plus vena cava filters are the appropriate therapy for hemodynamically unstable patients with pulmonary embolism
The American Journal of Medicine, Vol 125, No 5, May 2012 who face an approximately 50% mortality with standard anticoagulant therapy without vena cava filters. If there is a contraindication to thrombolytic therapy, pulmonary embolectomy (when feasible) plus a vena cava filter is the appropriate alternative. The 3 reports by Stein et al4 and Stein and Matta5,6 will lead to more effective treatment of patients with unstable pulmonary embolism. James E. Dalen, MD, MPH Dean Emeritus, University of Arizona College of Medicine Tucson
References 1. Kearon C, Kahn SB, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease. ACCP Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:454S-545S. 2. Dalen JE. Pulmonary embolism: what have we learned since Virchow?: treatment and prevention. Chest. 2002;122:1801-1817. 3. Kucher N, Rossi E, De Rosa M, et al. Massive pulmonary embolism. Circulation. 2006;113:577-582. 4. Stein PD, Matta F, Keyes DC, Willyerd GL. Impact of vena cava filters on in-hospital case fatality rates from pulmonary embolism. Am J Med. 2012;125:478-484. 5. Stein PD, Matta F. Thrombolytic therapy in unstable patients with acute pulmonary embolism: saves lives but underused. Am J Med. 2012;125:465-470. 6. Stein PD, Matta F. Case fatality rate with pulmonary embolectomy for acute pulmonary embolism. Am J Med. 2012;125:471-477. 7. Moretz WH, Rhode CM, Shepard MH. Prevention of pulmonary emboli by partial occlusion of the inferior vena cava. Am Surg. 1959; 25:617-626. 8. Stein PD, Matta F, Hull RD. Increasing use of vena cava filters for prevention of pulmonary embolism. Am J Med. 2011;124:655-661. 9. Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998;338: 409-415. 10. The Urokinase Pulmonary Embolism Trial. A national cooperative study. Circulation. 1973;47(Suppl 2):II-1-II-108. 11. Dalen JE, Alpert JS, Hirsh J. Thrombolytic therapy for pulmonary embolism: is it effective? Is it safe? When is it indicated? Arch Intern Med. 1997;157:2550-2556. 12. Dalen JE, Alpert JS. Pulmonary embolectomy. In: Dalen JE, ed. Venous Thromboembolism. New York: Marcel Dekker; 293-300.
Thrombolytics and Vena Cava Filters Decrease Mortality in Patients with Unstable Pulmonary Embolism SEE RELATED ARTICLES pp. 465, 471, and 478.
Standard anticoagulant therapy is very effective in patients with pulmonary embolism who are hemodynamically stable. Hospital mortality is in the range of 5% or less.1 However, in patients with shock secondary to massive pulmonary embolism, mortality ranges from 30% to 50%.2 A small minority of patients with pulmonary embolism present in shock. In a series of 2392 patients with pulmonary embolism, Kucher et al3 reported that only 4.5% of 2392 patients with pulmonary embolism had a systolic pressure less than 90 mm Hg and a hospital mortality of 52%. Three articles in this issue of The American Journal of Medicine by Stein et al4 and Stein and Matta5,6 provide impressive evidence that thrombolytics and vena cava filters, especially when used together, have a dramatic impact on the case fatality of patients with pulmonary embolism who are unstable, defined as in shock or requiring ventilator support. These studies are based on a review of all patients (⬎2 million) with acute pulmonary embolism who were discharged from 1000 US acute care hospitals over a 10- or 11-year period from 1999 to 2008. In their first article, Stein et al4 focus on the use of vena cava filters. Before the introduction of anticoagulants, the only treatment to prevent recurrent venous thromboembolism was ligation of the femoral veins. This was first performed by Homans in 1934.2 Homans later advocated ligation of the inferior vena cava, which had significant morbidity and mortality. Vena cava clips that partially occluded the vena cava, but prevented the passage of major emboli, were introduced by Moretz et al in 1959.7 MobinUddin2 developed an umbrella-like filter that could be introduced transvenously, thereby avoiding laparotomy. Further designs of filters have made them smaller, retrievable, and able to be introduced at the bedside with ultrasound guidance.8 The use of filters in the treatment and prevention of venous thromboembolism has accelerated in the United States from 2000 in 1979 to 92,000 in 2006.8 The American Funding: None. Conflict of Interest: None. Authorship: The author is solely responsible for the content of this manuscript.
0002-9343/$ -see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2011.09.023
College of Chest Physicians’ guidelines for antithrombotic and thrombolytic therapy only recommend inferior vena cava filters for patients with venous thromboembolism who have a contraindication to anticoagulants.1 Many clinicians recommend vena cava filters in patients who are hemodynamically unstable to reduce the risk of early recurrent embolism, which could be fatal in these critically ill patients. The one randomized clinical trial9 of vena cava filters plus anticoagulants compared with anticoagulants alone demonstrated a decreased rate of recurrent pulmonary embolism in the first 8 days of anticoagulant treatment. However, there was no decrease in mortality. It should be noted that these patients were not at high risk, and none were hemodynamically unstable and not all had pulmonary embolism. Stein et al4 reported that the mortality of 2 million patients with pulmonary embolism who were stable was 7.9% compared with 37% in the 72,230 patients who were unstable. The mortality in 38,000 unstable patients treated with standard anticoagulant therapy alone was 51% compared with 33% in 12,850 who had vena cava filters in addition to anticoagulants.4 This represents an impressive 35% decrease in the case fatality rate when vena cava filters are combined with standard anticoagulant therapy! In a second article, Stein and Matta5 focus on thrombolytic therapy. Thrombolytic therapy has been available since the Urokinase Pulmonary Embolism Trial in 197310 reported more rapid resolution of pulmonary emboli with urokinase than with heparin. However, there was no significant difference in mortality. Multiple reports since then have again shown a more rapid resolution of pulmonary embolism with tissue plasminogen activator.11 However, no randomized trials have reported a decreased mortality with thrombolytics compared with heparin in patients with hemodynamically unstable pulmonary embolism.1,11 The American College of Chest Physicians’ guidelines recommend thrombolytics for patients with pulmonary embolism if there is evidence of hemodynamic compromise and no major contraindications to thrombolytic therapy. This a grade 1B recommendation.1
430 Stein and Matta5 report that 21,390 patients with unstable pulmonary embolism received thrombolytics in addition to anticoagulants, and their mortality was 14.5% compared to 47% in those not receiving thrombolytics. The risk reduction was 69%. The results in 6630 unstable patients who received vena cava filters and thrombolytics were even more impressive. They had a fatality rate of 7.6% compared with 52% in 38,000 patients who received neither (85% risk reduction). The 7.6% mortality in the unstable patients who received a filter and thrombolytics was approximately the same (7.9%) as in 2 million stable patients treated with conventional anticoagulants. Stein and Matta6 examined the impact of pulmonary embolectomy on the mortality of those with unstable pulmonary embolism. Pulmonary embolectomy was first performed by Trendelenburg in 1908.12 It was the only known therapy for pulmonary embolism until the introduction of venous ligation in 1934.2 In 4 series with a total of 167 patients with massive pulmonary embolism and shock who underwent embolectomy between 1968 and 1997, the mortality was 35%.12 Stein and Matta6 reported that 950 patients with unstable pulmonary embolism underwent embolectomy between 1999 and 2008. The mortality was 40%. However, in 520 patients who had a filter in addition to embolectomy, the mortality was 25%.6 The findings in these 3 reports are not the result of randomized clinical trials. Given the fact that less than 5% of patients with pulmonary embolism are hemodynamically unstable, it is not surprising that randomized trials of vena cava filters or thrombolytics or embolectomy in patients with unstable pulmonary embolism have not been reported. It is highly unlikely that randomized trials of therapy for patients with unstable pulmonary embolism will ever be reported. These dramatic findings in the more than 72,000 patients who were treated for unstable pulmonary embolism in US hospitals from 1999 to 2008 indicate to this clinician that thrombolytic therapy (in those without contraindications) plus vena cava filters are the appropriate therapy for hemodynamically unstable patients with pulmonary embolism
The American Journal of Medicine, Vol 125, No 5, May 2012 who face an approximately 50% mortality with standard anticoagulant therapy without vena cava filters. If there is a contraindication to thrombolytic therapy, pulmonary embolectomy (when feasible) plus a vena cava filter is the appropriate alternative. The 3 reports by Stein et al4 and Stein and Matta5,6 will lead to more effective treatment of patients with unstable pulmonary embolism. James E. Dalen, MD, MPH Dean Emeritus, University of Arizona College of Medicine Tucson
References 1. Kearon C, Kahn SB, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease. ACCP Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:454S-545S. 2. Dalen JE. Pulmonary embolism: what have we learned since Virchow?: treatment and prevention. Chest. 2002;122:1801-1817. 3. Kucher N, Rossi E, De Rosa M, et al. Massive pulmonary embolism. Circulation. 2006;113:577-582. 4. Stein PD, Matta F, Keyes DC, Willyerd GL. Impact of vena cava filters on in-hospital case fatality rates from pulmonary embolism. Am J Med. 2012;125:478-484. 5. Stein PD, Matta F. Thrombolytic therapy in unstable patients with acute pulmonary embolism: saves lives but underused. Am J Med. 2012;125:465-470. 6. Stein PD, Matta F. Case fatality rate with pulmonary embolectomy for acute pulmonary embolism. Am J Med. 2012;125:471-477. 7. Moretz WH, Rhode CM, Shepard MH. Prevention of pulmonary emboli by partial occlusion of the inferior vena cava. Am Surg. 1959; 25:617-626. 8. Stein PD, Matta F, Hull RD. Increasing use of vena cava filters for prevention of pulmonary embolism. Am J Med. 2011;124:655-661. 9. Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998;338: 409-415. 10. The Urokinase Pulmonary Embolism Trial. A national cooperative study. Circulation. 1973;47(Suppl 2):II-1-II-108. 11. Dalen JE, Alpert JS, Hirsh J. Thrombolytic therapy for pulmonary embolism: is it effective? Is it safe? When is it indicated? Arch Intern Med. 1997;157:2550-2556. 12. Dalen JE, Alpert JS. Pulmonary embolectomy. In: Dalen JE, ed. Venous Thromboembolism. New York: Marcel Dekker; 293-300.