Thrombolysis in submassive pulmonary embolism

Abstract

Debates about the pros and cons of pulmonary embolism (PE) thrombolysis permeate academic meetings and journals. This tradition was initiated by Arthur Sasahara, the protagonist, and James Dalen, the antagonist, in 1980. The formula remains alive and well. Year 2003 featured a debate between Stavros Konstantinides vs. James Dalen in the inaugural issue of the Journal of Thrombosis and Haemostasis[1Konstantinides S. Thrombolysis in submassive pulmonary embolism? Yes.J Thromb Haemost. 2003; 1: 1127-9Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 2Dalen JE. Thrombolysis in submassive pulmonary embolism? No.J Thromb Haemost. 2003; 1: 1130-2Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar]. The American College of Chest Physicians continued this popular sport by hosting a debate between Dalen and me at its Scientific Session in Orlando in October 2003. Debates on this topic appeal to journal editors and conference organizers because they attract readers who cite the articles and increase the ‘impact factor’ and crowds at conferences who find the showdowns memorable and return to the meeting the following year, thereby boosting attendance. Yet, debates serve as poor substitutes for data. As a cardiologist, I emerge from a culture where we solve debates with rigorous clinical trials. Occasionally, the trials will involve hundreds of patients. For major issues such as the utility of thrombolysis, the trials have required enrollment of thousands and at times tens of thousands of patients. We enroll patients in the trials with the conviction that we will obtain a definitive ‘yes’ or ‘no’ answer to a fundamental clinical question. We choose the question by determining where there is disagreement among colleagues and clinical equipoise, with sufficient uncertainty that a thoughtful clinician can advocate randomization to each arm of a therapeutic strategy. With Coronary Care Units pervasive throughout the world, and with acute myocardial infraction (MI) easily identified by history, electrocardiogram, and cardiac biomarkers, we can find eligible patients efficiently and move forward. In the field of PE thrombolysis, we have only enrolled 771 patients in 10 randomized clinical trials of thrombolysis plus anticoagulation vs. anticoagulation alone. An overview indicates a possible 25% reduction in mortality, with very wide confidence intervals. The same overview demonstrates a doubling of major bleeding complications, with narrow confidence limits. I feel we are obligated to determine whether the hint of mortality reduction is real or due to the play of chance. If the benefit is illusory, we must curtail thrombolysis except for patients with massive PE. If real, however, we must coordinate protocols to enhance patient safety and minimize bleeding complications. Why have we moved so slowly to answer the PE thrombolysis debate? First, we who are interested in this issue are dispersed in many specialties and subspecialties. This makes trial organization more difficult. Second, PE itself may be difficult to detect because it mimics so many other illnesses. Third, the patients stricken with PE may have medical comorbidities that make them far from ideal candidates for this type of clinical trial. Fourth, thrombolytic agents are considered ‘mature drugs’, with commercial patents expiring and usage declining as percutaneous coronary intervention displaces thrombolysis as the routine management strategy for acute MI. Consequently, industry sponsorship is meager. Fifth, with regard to Federal funding, PE thrombolysis is not necessarily viewed as a high priority area compared with hot topics such as preventing bioterrorism. Nevertheless, the time for excuses has expired. Harry Büller has demonstrated that a large number of patients with symptomatic PE can be successfully recruited into an international randomized clinical trial of patients with acute symptomatic PE. He and his colleagues, the ‘Matisse Investigators’, enrolled 2213 patients to compare the efficacy and safety of fondaparinux with unfractionated heparin [3Büller H.R. Davidson B.L. Decousus H. Gallus A. Gent M. Piovella F. Prins M.H. Raskob G. Van Den Berg–Segers A.E. Cariou R. Leeuwenkamp O. Lensing A.W. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism.N Engl J Med. 2003; 349: 1695-702Crossref PubMed Scopus (825) Google Scholar]. We must follow his example to settle the PE thrombolysis question. By enrolling high‐risk patients with submassive PE, we can determine whether routine thrombolysis is worthwhile. Patients can now be diagnosed rapidly and accurately with chest CT scanning. Immediately after diagnosis, patients can be stratified to a high‐risk group despite normal blood pressure by using a combination of echocardiography [4Goldhaber SZ. Echocardiography in the management of pulmonary embolism.Ann Intern Med. 2002; 136: 691-700Crossref PubMed Google Scholar] and cardiac biomarkers [5Kucher N. Goldhaber SZ. Cardiac biomarkers for risk stratification of patients with acute pulmonary embolism.Circulation. 2003; 108: 2191-4Crossref PubMed Scopus (257) Google Scholar]. Randomization to thrombolysis plus anticoagulation vs. anticoagulation alone can then take place. Please let me know if you would like to collaborate in solving this enduring clinical question.