An In-Depth Review and Commentary on Important CT Literature

Donald Glower, MD

Review 2:

Abstract and Commentary by:  Donald Glower, MD

Heparin Plus Alteplase Compared With Heparin Alone in Patients With Submassive Pulmonary Embolism

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Konstantinides S, Geibel A, Heusel G, et al, for the Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators
N Engl J Med 2002;347:1143-50

Abstract

Use of thrombolysis in hemodynamically stable patients with acute submassive pulmonary embolism remains controversial.

The Management Strategies and Prognosis of Pulmonary Embolism-3 Trial prospectively randomized 256 patients at 49 centers in Germany.  Patients with acute pulmonary embolism and pulmonary hypertension or right ventricular dysfunction but without hypotension or shock received either heparin plus 100mg alteplase versus heparin plus placebo over a 2 hour period in a double blind fashion.  Endpoints were death or clinical deterioration of condition defined as catecholamine infusion, secondary thrombolysis, intubation, cardiopulmonary resuscitation, emergency surgical embolectomy, or percutaneous thrombus fragmentation.

Adverse combined endpoint was more likely in the placebo versus alteplase groups (P=0.005). Mortality was similar (3.4% placebo vs 2.2% alteplase, P =0.7), but treatment escalation was more frequent in the placebo versus alteplase group (24.6% vs 10.2%, P =0.004).  Death or treatment escalation was 2.6 times more likely in the placebo versus alteplase groups (P =0.006).   No cerebral bleed or fatal bleed occurred in the alteplase group.

When given with heparin, alteplase can prevent clinical deterioration requiring escalation of treatment in patients with acute submassive pulmonary embolism.

Comment

Prior studies have shown benefit from thrombolysis in patients with massive pulmonary embolism, and thrombolysis has therefore been recommended for massive thromboembolism.  In other patients with acute pulmonary embolism, anticoagulation alone is recommended.  Although the FDA approved the 2 hour alteplase regimen for acute pulmonary embolism in 1990, this is the first randomized trial to examine thrombolysis in acute submassive pulmonary embolism.1 It should be noted that patients with contraindications for thrombolysis were excluded from this study (age>80, recent surgery, recent trauma, recent gastrointestinal bleed, hypertension, bleeding disorder, life expectancy less than 6 months, or recent anticoagulation). The patients chosen for this study with pulmonary hypertension or right ventricular dilation have been shown to be a higher risk subgroup of all patients with acute pulmonary embolism. The main weakness of this high quality study is the soft endpoint that was used [1].  Thrombolysis still has not been shown to improve mortality from pulmonary embolism.

The role for surgical thrombectomy for acute pulmonary embolism remains controversial put is probably further diminished by less morbid alternatives such as thrombolysis in addition to anticoagulation.2  Some role for surgery in acute pulmonary thromboembolism might exist in those patients with proximal pulmonary artery thrombus, hemodynamic compromise, and contraindication to thrombolysis. Such surgical candidates are a very small subset of all patients with acute pulmonary embolism.

Figure 1
 

Fig 1. Kaplan-Meier estimates of the probability of event-free survival among patients with acute submassive pulmonary embolism, according to treatment with heparin plus alteplase or heparin plus placebo.  An event was defined as in-hospital death or clinical deterioration requiring an escalation of treatment after termination of the infusion of the study drug. Escalation of treatment was defined as at least one of the following: infusion of a catecholamine because of arterial hypotension or shock (except for dopamine infused at a rate of no more than 5 mg per kilogram per minute), secondary thrombolysis, endotracheal intubation, cardiopulmonary resuscitation, or emergency surgical embolectomy or thrombus fragmentation by catheter.  P = 0.005 by the log-rank test for the overall comparison between the groups. (Reprinted with permission from N Engl J Med 2002;347:1143-50 Copyright © 2002 Massachusetts Medical Society. All rights reserved.)

References

  1. Goldhaber SZ.  Thrombolysis for pulmonary embolism.  N Engl J Med 2002;347:1131-2.
     
  2. Fam NP, Verma A.  Thrombolysis of a massive pulmonary embolism. N Engl J Med 2002;347;1161.

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