Recommendations for appropriate administration of thrombolysis in PE have sparked debate and controversy for the past 30 years. Sometimes, those preparing journal symposia or national meetings have successfully enlivened their projects by inviting a “protagonist” and “antagonist” of thrombolysis for PE to pummel each other in public. Such exercises naturally tend to make the debaters focus solely on points that support their assigned positions. As a result, the audience must contend with two extreme views that rarely overlap. In contrast, consensus conferences have been convened to obtain expert opinions and then to issue guidelines on the optimal role of thrombolysis in PE management. Unfortunately, neither debates nor consensus conferences help to advance the field very much because the “take home message” is often swayed more by the articulateness and authority of a particular individual than by literature-based evidence. Ironically, the written or oral debate format and consensus guidelines are often relied on the most when data are sparse and the field of interest is murky.
Instead of becoming immolated by the heat of argument, one should pause when considering PE thrombolysis so that several fundamental points can be enumerated. First, PEs present with a wide spectrum of acuity and differ markedly in size and physiological effects. Therefore, optimal management strategies should rely on risk stratification rather than a “one size fits all” approach to treatment.1 Second, PE patients are often cursorily dichotomized as having either hemodynamic instability (with a systolic arterial pressure <90 mm Hg) or “normal hemodynamics.” However, cardiologists especially should further categorize patients as having normal systemic arterial pressure plus normal right ventricular function or normal systemic arterial pressure plus dysfunction of the right ventricle. The latter population, which was the focus of the study by Konstantinides and colleagues2 in this issue of Circulation, may well benefit from thrombolysis even though a final verdict has not yet been rendered. Although the phrase “hemodynamically stable” was used in the title of their report, these patients were not really hemodynamically stable because they had pulmonary hypertension and/or right ventricular dysfunction as a consequence of PE.
Few cardiologists would withhold thrombolysis from a PE patient in cardiogenic shock unless there were major contraindications to this potent but potentially risky pharmacological option. In one small trial, thrombolysis proved to be lifesaving in patients with massive PEs, hypotension, and heart failure who were randomized to thrombolysis plus anticoagulation rather than to anticoagulation alone. Because of ethical considerations resulting from a clear survival benefit in the thrombolysis group, the trial was stopped after the first 8 of 40 intended patients were enrolled.3 All 4 patients who received thrombolysis survived massive PEs. However, all 4 of the patients allocated to the anticoagulation alone group died of progressive failure of the right side of the heart, and the 3 who underwent postmortem examination had right ventricular myocardial infarctions (without significant coronary arterial obstruction), undoubtedly because of their massive PEs.
At the other extreme, the risks of thrombolysis are not warranted in the treatment of patients with anatomically small PEs that cause no elevation in pulmonary artery pressure and no right ventricular dysfunction. In an overview of 5 PE thrombolysis trials that our research group has conducted over the past decade, 4 of 312 patients suffered intracranial hemorrhage within 24 hours of receiving rt-PA or urokinase. Of these 4 patients, 2 died of hemorrhagic stroke. Of the 2 survivors, 1 had a history of seizures and received thrombolysis in violation of the protocol. Overall, we found that the presence of systemic arterial diastolic hypertension at the time of hospital admission increased the risk of intracranial hemorrhage. Notably, no patient <57 years of age suffered hemorrhagic stroke.4
The “middle group,” with normal systemic arterial pressure and right ventricular dysfunction, constitutes those PE patients who generate the most controversy over whether thrombolysis should be administered. We coordinated a trial of 101 PE patients randomized to rt-PA 100 mg/2 h followed by heparin or to heparin alone.5 All presented with normal systemic arterial pressure, and slightly less than half had right ventricular dysfunction on echocardiogram. Of the patients assigned to rt-PA followed by heparin, none died or had recurrent PEs. In contrast, among the 55 patients who received heparin alone, 5 had recurrent PEs despite therapeutic levels of anticoagulation, and 2 of these 5 PEs were fatal (P=.06). All 5 were treated with heparin alone and presented with a combination of normal systemic arterial pressure plus echocardiographic evidence of right ventricular hypokinesis.
The mechanism for clinical improvement is uncertain. Perhaps right ventricular dysfunction is a surrogate for a large clot burden. Possibly, thrombolysis dissolves the source of the clot in the pelvic or deep leg veins, thus reducing the rate of recurrent PE. If right ventricular contractile dysfunction continues unabated, right ventricular cardiac output will decrease and will further reduce left ventricular preload. With underfilling of the left ventricle, systemic cardiac output and pressure both decrease, potentially compromising coronary perfusion and producing myocardial ischemia (the Figure⇓). Perpetuation of this cycle can lead to myocardial infarction, circulatory collapse, and death.6
With increasingly large perfusion defects on scan, the likelihood of right ventricular failure increases. We have found that performing echocardiograms on normotensive patients is especially worthwhile for detecting right ventricular dysfunction when more than one third of the entire lung scan is underperfused.7
Despite calls for international collaboration to undertake a definitive thrombolysis trial,8 the organization of such a mammoth undertaking would be arduous, expensive, and painstaking. In the meantime, observational registries can provide us with hypotheses that are “ripe” for subsequent testing in a randomized controlled design. Although logistical coordination of a successful registry can be extremely challenging, patients can be enrolled at a much faster rate than in a randomized controlled trial once the registry is under way.
The investigators who coordinated MAPPET undertook a most ambitious observational study with 204 centers that enrolled 1001 consecutive PE patients with right-heart failure and/or pulmonary hypertension caused by PE.2 Patients were enrolled over a 15-month period. This registry therefore deserves special recognition as the largest published registry of its kind. All patients had major PEs, and approximately one third were excluded from the Konstantinides et al2 study because of cardiogenic shock that would have warranted thrombolysis or embolectomy in most instances. Thus, the MAPPET investigators, under the leadership of Wolfgang Kasper, chose to study those PE patients in whom use of thrombolysis generates the most controversy.
When interpreting the results of registry data, it is imperative to keep in mind that the two groups being compared (in this case, the thrombolysis group and the heparin group) may very well not be comparable. As the investigators themselves clearly state, “With such an observational design, selection bias is likely.” Indeed, one suspects that in MAPPET, the heparin group, which was made up of three fourths of the patients described in the registry, was sicker and would have had a worse prognosis even if thrombolysis had been withheld or administered to all participants in the registry. Although a multivariate analysis was performed, the baseline differences are impressive. The heparin group was older, was twice as likely to have congestive heart failure, and was more than three times as likely to have chronic pulmonary disease. Nevertheless, during hospitalization, the rate of adverse outcomes was strikingly lower among thrombolysis-treated patients. The death rate at 30 days was 5% for thrombolysis patients (versus 11% for heparin alone patients), and the recurrent PE rate during hospitalization was 8% (versus 19% for heparin alone patients). It is important to note that in addition to the 24% of patients who initially received thrombolysis within 24 hours, another 23% subsequently “crossed over” to thrombolysis from the heparin alone group.
The penalty paid for initial use of thrombolysis was a threefold higher rate of major bleeding (22%) compared with the heparin group. The intracranial hemorrhage rate in the thrombolysis group was 1.2%. One of the two intracranial hemorrhages was fatal. Thus, MAPPET re-creates the same tension that exists in other thrombolysis studies between the advantage of improved clinical efficacy and the hazard of increased bleeding complications.
Despite its limitations, MAPPET provides additional ammunition for those who champion the hypothesis that thrombolysis will benefit PE patients who present with normal systemic arterial pressure but who have right ventricular dysfunction on echocardiogram. MAPPET is a valuable contribution to the field, especially because it focuses on the most controversial population of potential PE thrombolysis patients. However, the debate is far from over.
Those interested in this field should be aware of the International Cooperative Pulmonary Embolism Registry.9 The results from this seven-country, 50-institution registry will comprise approximately 2500 PE patients and should be available for presentation at the 1997 American Heart Association Scientific Sessions. This international registry enrolls all consecutive PE patients at participating centers, without regard to the presence of right ventricular dysfunction or pulmonary hypertension. It is clear that a substantial proportion of these patients are receiving echocardiograms as part of their routine clinical care. A subanalysis of right ventricular dysfunction patients, stratified according to lack of hypotension and use of thrombolysis, will be most interesting with respect to outcomes such as death and recurrent PE.
In the absence of a definitive randomized trial, what should cardiologists recommend when evaluating PE patients who have the triad of no contraindications to thrombolysis, normal systemic arterial pressure, and moderate or severe right ventricular dysfunction? We currently favor administration of thrombolysis to patients who fit this three-part profile as well as to patients in cardiogenic shock. Fortunately, the administration of thrombolysis to PE patients has become streamlined, safer, and less expensive over the past few years.10 A practical treatment regimen of rt-PA (100 mg IV as a continuous peripheral infusion over 2 hours) was approved in 1990 by the Food and Drug Administration. Bleeding complications can be minimized by meticulous history taking before thrombolysis is administered to determine whether there are clinical risk factors for intracranial hemorrhage such as prior uncontrolled hypertension, stroke, or seizure disorder. Costs can be reduced by eschewing testing of fibrinogen, fibrin(ogen) split products, and thrombin time.
Regardless of whether thrombolysis is used, the cardinal principles of risk stratification (by determining whether right ventricular dysfunction exists) and risk assessment for intracranial hemorrhage should be integrated into the contemporary management of acute PE.
Selected Abbreviations and Acronyms
|MAPPET||=||Management Strategy and Prognosis of Pulmonary Embolism Registry|
|rt-PA||=||recombinant tissue plasminogen activator|
|STRIPE||=||Streptokinase in Pulmonary Embolism|
The opinions expressed in this editorial are not necessarily those of the editor or the American Heart Association.
- Copyright © 1997 by American Heart Association
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