Evidence Based Review Article

The Journal of Informed Pharmacotherapy 2003;12:201.

Heparin Alone or Combined with Alteplase for Patients with Submassive Pulmonary Embolism: Are Two Agents Better than One?


Reviewer: Peter J. Zed, B.Sc., B.Sc.(Pharm), Pharm.D.
Reviewer’s e-mail address: zed@interchange.ubc.ca

Reviewer's profession/specialty: Pharmacotherapeutic Specialist - Emergency Medicine

Original Citation

Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347:1143-50. PubMed Citation

Overall Study Question

This trial was conducted to determine the efficacy of unfractionated heparin (UFH) plus tissue plasminogen activator (tPA) compared to UFH alone in patients with acute submassive pulmonary embolism (PE). Adult patients with PE and one of either, echocardiographically determined right ventricular dysfunction, pulmonary hypertension or both without hemodynamic instability were eligible for the study. The primary endpoint was in-hospital mortality or clinical deterioration that required an "escalation of treatment" after the infusion of study drug.  These were assessed at the end of hospital stay or on day 30 following randomization, whichever occurred earlier. The secondary endpoints included recurrent PE, major bleeding and ischemic stroke

An "escalation of treatment" was defined as the use of at least one of the following: 1) an infusion of a cathecholamine because of persistent arterial hypotension or shock; 2) secondary or "rescue" thrombolysis; 3) endotracheal intubation; 4) cardiopulmonary resuscitation and; 5) emergency surgical embolectomy of thrombus fragmentation by catheter.

Are the Results of the Study Valid?

1. Was assignment of patients randomized?

Yes. All patients received unfractionated heparin (UFH) 5000 U bolus followed by 1000 U/h to maintain the activated partial thromboplastin time 2.0-2.5 times upper limit of normal.  Patients were then randomized to receive either 100 mg of tPA given as a 10 mg IV bolus, followed by 90 mg infusion over 2 hours, or matching placebo.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Yes. 256 patients met inclusion criteria and were randomized (118 tPA/UFH and 138 UFH).  All patients were included in the final analysis.

3. Were patients, their clinicians, and study personnel 'blind' to treatment?

Yes. The study was double-blinded.

4. Were the groups similar at the start of the trial?

Yes. The two groups were well-matched with regard to measured baseline characteristics.

5. Aside from the experimental intervention, were the groups treated equally?

Yes. There were no differences in the further treatment of patients assigned to tPA/UFH or UFH alone.

What were the Results?

1. How large was the treatment effect? 

The primary endpoint, in-hospital mortality or clinical deterioration, occurred in 11.0% of patients treated with tPA/UFH compared to 24.6% of patients who received UFH alone (p=0.006).  This represents an absolute risk reduction (ARR) of 13.6% and a number needed to treat of 8.  There was no difference in in-hospital mortality between the two groups (3.4% tPA/UFH vs. 2.2% UFH, p=0.71) but escalation of treatment occurred less commonly in the tPA/UFH-treated patients compared to UFH alone at 10.2% and 24.6%, respectively (p=0.004).  Administration of secondary or "rescue" thrombolysis occurred in 7.6% of tPA/UFH-treated patients compared to 23.2% of UFH-treated patients (p=0.001).

The secondary endpoints of recurrent PE, major bleeding and ischemic stroke were not different between the two groups.

2. How precise was the estimate of the treatment effect?

The relative risk of an unfavourable primary endpoint with UFH compared to tPA/UFH was 2.63 (p=0.006); however, the 95% CI was not provided.

Will the Results Help Me in Caring for My Patients?

1. Can the results be applied to my patient care?

Yes.  The use of tPA in addition to UFH to manage patients with submassive PE (pulmonary hypertension, RV dysfunction, or both) without hemodynamic compromise reduced the likelihood of clinical deterioration but had no impact on reducing overall mortality.

2. Were all clinically important outcomes considered?

Yes. 

3. Are the likely treatment benefits worth the potential harms and costs?

Unknown. Many questions still remain unanswered regarding the use of thrombolytics in the treatment of submassive PE.  Although this trial demonstrated a reduction in the primary endpoint, this was entirely attributed to a reduction in the number of patients experiencing clinical deterioration without any apparent benefit on overall in-hospital survival. In addition, although the bleeding rates were similar between groups, the study population was too small to accurately evaluate major bleeding complications.  Accordingly, we must be cautious in our interpretation of the relative bleeding risk identified in this small trial.  Finally, the economic implications of using tPA for the management of submassive PE were not evaluated by these investigators.

Commentary

The use of thrombolytics in the management of massive and submassive PE has not been well studied.  Thrombolytic therapy with tPA in addition to UFH in patients with massive PE and hemodynamic instability does appear to achieve a more rapid resolution of thromboembolism and resolution of lung scan abnormalities and hemodynamic compromise when compared to UFH alone or to streptokinase (SK) (1-3). However, there is no clearly established short-term mortality reduction with thrombolytics for PE.  In addition, patients who receive thrombolytic therapy for PE have a 1-2% risk of intracranial hemorrhage.  Consequently, recent published recommendations state that thrombolytic therapy should be reserved for patients with acute massive PE with hemodynamic instability and at low risk for bleeding (4). 

The use of thrombolytics in patients with submassive PE without hemodynamic compromise is more controversial than in patients with massive PE and hemodynamic compromise (5-6).  As described by Goldhaber, proponents of thrombolysis claim a potential survival benefit, fewer recurrences of pulmonary embolism, long-term prevention of pulmonary hypertension, and improved quality of life. (5)  Conversely, Opponents contend that the bronchial collateral circulation provides continued pulmonary perfusion and usually makes thrombolysis unnecessary in patients with pulmonary embolism.  They cite complications of thrombolysis (especially intracranial hemorrhage), an increased use of hospital resources (e.g. beds in the intensive care unit), and a more extensive use of laboratory tests.  They also note that most patients who are treated with anticoagulation alone will catch up with thrombolysis-treated patients within several days.  Most importantly, they remind us once again that trials of thrombolysis for pulmonary embolism have not shown decreased mortality rates or decreased rates of recurrence (7). 

Similarly, the results of this trial suggest that, while thrombolysis with tPA reduces the likelihood of further clinical deterioration, it fails to demonstrate a short-term mortality benefit.  One of the unanswered questions in the management of PE is the choice of thrombolytic agent.  As mentioned above, tPA does appear to achieve more rapid response compared to SK in the setting of massive PE.  In addition, tPA has a lower incidence of hypotension than SK, making this agent more attractive in the setting of hemodynamic compromise.  However, it is unknown whether or not these advantages apply to patients with submassive PE without hemodynamic compromise.  At approximately $2,700 (CAN) per tPA treatment course, as compared to $250 (CAN) for SK, it would be beneficial to determine the relative benefit and safety of each agent and the associated economic implications in this patient population.

In summary, tPA demonstrated benefit in this trial in reducing further clinical deterioration in patients with submassive PE without hemodynamic compromise; however, further study is necessary to further characterize those patient populations that are most likely to benefit and least likely to experience bleeding complications; and to determine which thrombolytic agent offers the most appropriate choice.

Reviewer Competing Interests

None declared.

References 

  1. Dalen JE, Alpert JS, Hirsch J. Thrombolytic therapy for pulmonary embolism: is it effective: Is it safe? When is it indicatd? Arch Intern Med 1997;157:2550-60.
  2. Meneveau N, Schiele F, Vuillemenot A, et al. Streptokinase vs. alteplase in massive pulmonary embolism. Eur Heart J 1997;18:1141-8. 
  3. Meneveau N, Schiele F, Metz D, et al. Comparative efficacy of a two-hour regimen of streptokinase versus alteplase in acute massive pulmonary embolism: intermediate clinical and hemodynamic outcome and one-year follow-up. J Am Coll Cardiol 1998;31:1057-63. 
  4. Hyers TM, Agnelli G, Hull R, et al. Antithrombotic therapy for venous thromboembolic disease. Chest 2001;119(Suppl):176S-193S. 
  5. Goldhaber SZ. Thrombolysis in pulmonary embolism: a debatable indication. Thromb Haemost 2001;86:444-51.  
  6. Konstantinides S, Geibel A, Kasper W. Submassive and massive pulmonary embolism: a target for thrombolytic therapy? Thromb Haemost 1999;82(Suppl 1):104-8. 
  7. Goldhaber SZ. Thrombolysis for Pulmonary Embolism. N Engl J Med 2002;347:1131-2.

Copyright © 2003 by the Journal of Informed Pharmacotherapy. All rights reserved.