Are Thrombolytics Needed in Submassive Pulmonary Embolism?
Abstract & Commentary
In this randomized, double-blind study, 256 patients with submassive pulmonary embolism (PE) were treated with either heparin or heparin plus alteplase, a thrombolytic agent. Konstantinides and associates included patients who had acute PE associated with any one of the following: 1) echocardiographically detected right ventricular dysfunction (right ventricular enlargement combined with loss of inspiratory collapse of the inferior vena cave, without left ventricular dysfunction or mitral valve disease); 2) echocardiographically detected pulmonary-artery hypertension, defined as a tricuspid regurgitation jet greater than 2.8 m/sec followed by confirmation of PE diagnosis (with ventilation-perfusion scan, computed tomography, or pulmonary arteriogram); 3) right heart catheterization and diagnosis of pulmonary-artery hypertension with mean pulmonary artery pressure > 20 mm Hg and wedge pressure < 18 mm Hg followed by confirmation of PE diagnosis; or 4) new electrocardiographic evidence of right ventricular strain (complete or incomplete right bundle branch block, S waves in lead I combined with Q waves in lead III or inverted T waves in precordial leads V1,V2, and V3) followed by confirmation of PE diagnosis. Exclusion criteria were age > 80 years, hemodynamic instability with or without cardiogenic shock, onset of symptoms more than 96 hours prior to diagnosis, thrombolytic treatment or major surgery or biopsy within past 7 days, major trauma in past 10 days, central nervous system events in preceding 6 months, and others including pregnancy and limited life expectancy.
In a block-of-6 randomization design, 118 patients were assigned to the heparin-plus-alteplase group and 138 patients were assigned to the heparin-plus-placebo group. Patients in both groups were comparable for baseline parameters including age, sex, gender, weight, blood pressure at baseline, baseline PaO2, incidence of right ventricular dysfunction by echocardiography (31%), and comorbid conditions. Fifty-five percent of the patients in the placebo group had an S1-Q3 pattern on EKG, compared to 34% of patients in the alteplase group. Approximately 17% of the patients had right heart catheterization with comparable pulmonary artery pressures (systolic around 55 mm Hg, mean PA pressure around 35 mm Hg). Nearly 90% of the study patients had echocardiography, with mean tricuspid regurgitation velocity jet exceeding 3 m/sec in both groups.
The trial was designed with a composite primary end point and multiple secondary end points. The primary end point was mortality or escalation of therapy (use of catecholamines except dopamine < 5 mcg/kg/min; secondary thrombolysis for worsening dyspnea or respiratory failure or persistent right ventricular dysfunction or worsening pulmonary hypertension; endotracheal intubation; cardiopulmonary resuscitation; or need for embolectomy or thrombus fragmentation) at 30 days or hospital discharge, whichever happened first. Secondary end points included recurrent pulmonary embolism, major bleeding, or ischemic stroke. Konstantinides et al report that the incidence of attaining the primary end point (death or escalation of therapy) was significantly lower in the heparin-plus-alteplase group (13 patients, 11%) as compared to heparin-plus-placebo group (34 patients, 24.6%; P = 0.006).
The majority of the patients attaining the primary end point in the heparin-plus-placebo group were patients who had escalation of treatment, especially in the form of secondary thrombolysis for hypotension, cardiogenic shock, or "worsening symptoms." There was 1 fatal bleeding complication in the heparin-plus-placebo group and no such event in the alteplase-heparin group. Mortality was low in both groups. Overall, 3.4% of the patients died in the heparin-alteplase group, as compared to 2.2% in the heparin-placebo group. Konstantinides et al conclude that alteplase, in a dose of 10 mg bolus followed by additional 90 mg over 2 hours, is safe and effective at improving event-free survival in submassive PE (Konstantinides S, et al. Heparin plus alteplace compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002;347[15]:1143-1150).
Comment by Uday B. Nanavaty, MD
PE is a common disorder that critical care specialists deal with in everyday life. It is a disorder, like many others, which is better prevented than treated. It is widely believed that PE is often underdiagnosed. However, with widespread use and increasing experience with spiral CT scans (CT angiography), the diagnosis of PE has become quite reliable and easy. The treatment of thromboembolic disease has also been facilitated in recent years as low-molecular-weight heparin therapy has gained more widespread use. However, thrombolytic agents for treatment of PE have not gained wide acceptance. There are limited data on the superiority of thrombolytic agents in massive PE. Without any other therapy available for patients with hemodynamic compromise, thrombolytic agents are used in selected patients, especially those without significant comorbidities. The number of patients who get thrombolytics for massive PE remains small in part because of the complications of the thrombolytic therapy. Also, the right ventricular failure and systemic hypotension often improve by the time a diagnosis is established, as the saddle embolus that produces acute obstructive shock often fragments without therapy.
This study was performed to address the group of patients with submassive PE. The study population was rather heterogeneous. The study results suggest that alteplase is safe in this population of patients. What is not clear to me is whether it is really necessary to treat this group of patients with thrombolytics. Mortality in this group of patients was only 2.5% or so. There were no major bleeding problems with alteplase. These patients seem not to die from their PE at least as suggested by Konstantinides et al. The biggest problem in my mind with the study is the composite primary end point. There is no mortality advantage with use of alteplase. The composite primary end point of escalation of therapy does not in my mind justify the therapy. There are clearly some patients who will have submassive PE who may benefit from thrombolytics, but, unfortunately, which patients those are is not clear to me from this study.
Until particular subgroups are identified, I would use thrombolytics very judiciously, on a case-by-case basis. This study does provide further hope that some day we will be able to identify that subgroup of patients with submassive PE in whom thrombolytic therapy could safely be used. Until then, I would use all the exclusion criteria strictly to identify a group of patients with sub massive PE where alteplase is safe, and then see if there are factors, such as worsening hypoxemia or hemodynamic compromise or other unequivocal evidence that thromboembolic disease is worsening, to initiate the thrombolytic therapy, very carefully.
Dr. Nanavaty of Pulmonary and Critical Care Specialists of Northern Virginia, Fairfax, VA.
In this randomized, double-blind study, 256 patients with submassive pulmonary embolism (PE) were treated with either heparin or heparin plus alteplase, a thrombolytic agent.Subscribe Now for Access
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