Am Fam Physician. 2002 Aug 15;66(4):560-563.
to the editor: We read with interest Dr. Almoosa's article, “Is Thrombolytic Therapy Effective for Pulmonary Embolism?”,1 and would like to comment on some points. Thrombolytic therapy results in more clot lysis than treatment with heparin alone.2 However, both treatments produce similar improvement in pulmonary perfusion.2 So, the answer to the title question is, yes, thrombolytic therapy is effective for pulmonary embolism (PE). What remains debatable are the indications of thrombolytic agents in PE.
Dr. Almoosa states that no evidence from clinical trials proves thrombolytic therapy reduces the recurrence rate of pulmonary embolism or affects mortality better than anticoagulation. This fact needs to be put in historical and statistical context. Early trials have limited relevance in the era of modern thrombolytic agents. The majority of these early studies did not have sufficient sample power to detect small but clinically relevant improvements in mortality. The randomized, multicenter American study3 was only capable of demonstrating a mortality benefit greater than 15 to 20 percent. Lesser reductions would not have been detected. Other trials showed a trend toward reduction in mortality in the group treated with thrombolysis, but mortality was not significantly altered.4 If more patients had been included, statistical significance might have been reached.
One small trial5 has shown a dramatic survival advantage favoring thrombolytic therapy in patients with massive PE and systemic hypoperfusion. Those patients are now considered to have an absolute indication for thrombolytic therapy.2 Therefore, the appropriate treatment for PE should be based on risk stratification rather than a global approach. Among hemodynamically stable patients, those with anatomically small clots that cause no elevation in pulmonary artery pressure and no right ventricular dysfunction, the potential advantages of thrombolysis are counterbalanced by its risks and costs. The appropriate treatment in such patients remains heparin anticoagulation.
Patients with normal hemodynamic parameters but right ventricular dysfunction generate the most controversy with regard to treatment.2 Right ventricular dysfunction clearly defines patients at high risk for clinical deterioration, and these patients are excellent candidates for thrombolytic therapy.3 A recent trial6 that evaluated 719 patients with right ventricular dysfunction reported a 30-day mortality of 11.1 percent in the anticoagulant group, compared with 4.7 percent in the thrombolytic group. Most important, a statistically significant reduction was achieved in the rate of PE recurrence (which may even be fatal): 18.7 percent versus 7.7 percent, in the thrombolytic group and anticoagulant group, respectively. Although this trial was not randomized, the results might have some validity. As with acute myocardial infarction, one would expect that a larger (more than 1,000 patients) randomized multicenter study will eventually give the definitive indications for thrombolytic therapy in such patients.
1. Almoosa K. Is thrombolytic therapy effective for pulmonary embolism? Am Fam Physician. 2002;65:1097–102.
2. Arcasoy SM, Kreit JW. Thrombolytic therapy of pulmonary embolism. A comprehensive review of current evidence. Chest. 1999;115:1695–707.
3. Goldhaber SZ, Haire WD, Feldstein ML, Miller M, Toltzis R, Smith JL, et al. Alteplase versus heparin in acute pulmonary embolism: randomized trial assessing right-ventricular function and pulmonary perfusion. Lancet. 1993;341:507–11.
4. Suspected acute pulmonary embolism: a practical approach. British Thoracic Society, Standards of Care Committee. Thorax. 1997;52(suppl 4):S1–24.
5. Jerjes-Sanchez C, Ramirez-Rivera A, de Lourdes Garcia M, Arriaga-Nava R, Valencia S, Rosado-Buzzo A, et al. Streptokinase and heparin versus heparin alone in massive pulmonary embolism: a randomized controlled trial. J Thromb Thrombolysis. 1995;2:227–9.
6. Konstantinides S, Geibel A, Olschewski M, Heinrich F, Grosser K, Rauber K, et al. Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry.
in reply: I appreciate the comments made by Drs. Mofredj, Baraka, and Beldjoudi. There is little disagreement on administering thrombolytics to patients with hemodynamically unstable pulmonary embolism (PE), and anticoagulation to patients with PE who have no evidence of right ventricular (RV) dysfunction. However, controversy arises when thrombolytics are considered for patients with stable PE who have RV dysfunction. Older studies cannot be used to clarify this issue for two reasons: (1) these studies did not effectively stratify patients according to severity or risk; and (2) modern medical technology and a deeper understanding of the pathophysiology and outcomes of various subgroups of patients with PE have changed our approach and level of aggressiveness to these patients while improving our ability to manage complications.
Unfortunately, despite calls for larger trials, there is still a paucity of conclusive clinical studies that offer clear, evidence-based indications and criteria for this potentially damaging intervention. The trials that do recommend thrombolytics for patients with stable PE who have RV dysfunction are either insufficiently powered, lack randomization, or produced results that have not been confirmed in larger repeat trials.1–3 Until larger, more specific controlled trials show significant evidence of improvement in major outcomes, use of this therapy will continue to cause disagreement and debate. What keeps me from recommending thrombolytics for the previously healthy 40-year-old woman, for example, with a new, hemodynamically stable PE and RV dysfunction, is the possibility of her developing a stroke or bleeding to death, especially in view of the fact that she will most likely do just as well with heparin therapy alone.
1. Konstantinides S, Geibel A, Olschewski M, Heinrich F, Grosser K, Rauber K, et al. Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry. Circulation. 1997;96:882–8.
2. Levine M, Hirsh J, Weitz J, Cruickshank M, Neemah J, Turpie AG, et al. A randomized trial of a single bolus dosage regiment of recombinant tissue plasminogen activator in patients with acute pulmonary embolism. Chest. 1990;98:1473–9.
3. Dalla-Volta S, Palla A, Santolicandro A, Giuntini C, Pengo V, Visioli O, et al. PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen activator Italian multicenter study 2. J Am Coll Cardiol. 1992;20:520–6.
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