Correspondence
Thrombolytic Therapy in Patients with Submassive Pulmonary Embolism
N Engl J Med 2003; 348:357-359January 23, 2003
- Article
To the Editor:
Konstantinides et al. (Oct. 10 issue)1 evaluated the role of alteplase in patients with submassive pulmonary embolism. Their findings will be regarded by many as definitive evidence in support of the use of thrombolytic agents in such patients. However, a review of the study design, particularly the end points chosen, shows that the data do not support the authors' conclusions.
The only primary end point to show significant improvement was an escalation of treatment for clinical deterioration — nearly always meaning treatment with open-label alteplase, the drug used in the intervention group. The decision to escalate treatment was made by clinicians, who were permitted to break the randomization code first; thus, the primary end point in a given case could be determined by an unblinded provider. Escalation of treatment would have been unlikely in a patient with clinical deterioration who was in the alteplase group but would have been likely in a patient with similar deterioration who was in the placebo group.
The study suggests that the number needed to treat was nine; in other words, nine patients would have to be given alteplase to avoid treatment escalation (i.e., use of open-label alteplase) in one patient. In view of the 1 percent risk of major hemorrhage with thrombolysis,2 avoiding open-label use in one patient hardly justifies preemptive use of the drug in many more patients.
2 ReferencesRendell W. Ashton, M.D.
Craig E. Daniels, M.D.
Jay H. Ryu, M.D.
Mayo Clinic, Rochester, MN 559011
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;347:1143-1150
Full Text | Web of Science | Medline2
Marder VJ ,Stewart D . Toward safer thrombolytic therapy. Semin Hematol 2002;39:206-216
CrossRef | Web of Science | Medline
To the Editor:
Konstantinides et al. purportedly demonstrate a significant clinical benefit of thrombolysis in patients with submassive pulmonary embolism. However, we believe a more subtle conclusion can be reached.
The authors' primary end point was a composite of clinical deterioration requiring an escalation of treatment and death. Although the incidence of the composite end point differed significantly between the study groups, the difference appears to be due to escalation of treatment in a larger number of patients in the placebo group. This escalation can be entirely accounted for by the use of secondary thrombolysis in patients whose clinical condition was thought to be deteriorating.
The authors state, “The trial protocol permitted breaking of the randomization code if additional therapy had to be provided on an emergency basis to a patient whose condition was deteriorating.” In other words, if a patient's condition was deteriorating, one could determine whether the patient had received thrombolytic therapy or placebo and thereafter decide whether to give the patient alteplase. Most reasonable clinicians who realized that a patient with clinical deterioration had received placebo would administer thrombolytic agents. Thus, the unblinding of randomization status undermines the validity of the statistically significant difference in the end point between the groups.
Although this study does not demonstrate a significant difference in rates of major bleeding, a finding that supports the safety of alteplase, the principal conclusion that can be drawn from the study is that the use of alteplase for submassive pulmonary embolism decreases the frequency of the use of thrombolytic therapy later in the hospital course.
Nathaniel A. Gunn, M.D.
Lawrence M. Tierney, Jr., M.D.
University of California at San Francisco, San Francisco, CA 94143
ngunn@medicine.ucsf. edu To the Editor:
Inadequate anticoagulation with heparin may explain the apparent superiority of alteplase over placebo for the treatment of submaximal pulmonary embolism, as reported by Konstantinides et al. The mean activated partial-thromboplastin time was significantly lower in the placebo group than in the alteplase group during the first six hours after randomization. Previous clinical trials have established the superiority of a weight-based heparin nomogram over the protocol used by Konstantinides et al. (a bolus of 5000 units of unfractionated heparin, followed by 1000 units per hour).1
Patients treated for venous thromboembolism who have subtherapeutic partial-thromboplastin times during the first 24 hours of treatment have an increased risk of recurrent events.2 It would be interesting to know how many patients who reached the primary end point in the trial conducted by Konstantinides et al. had subtherapeutic partial-thromboplastin times.
2 ReferencesDavid A. Berlin, M.D.
Weill Medical College of Cornell University, New York, NY 10021
berlind-d@lycos.com 1
Raschke RA ,Reilly BM ,Guidry JR ,Fontana JR ,Srinivas S . The weight-based heparin dosing nomogram compared with a “standard care“ nomogram: a randomized controlled trial. Ann Intern Med 1993;119:874-881
Web of Science | Medline2
Hull RD ,Raskob GE ,Brant RF ,Pineo GF ,Valentine KA . Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis. Arch Intern Med 1997;157:2562-2568
CrossRef | Web of Science | Medline
To the Editor:
The most striking finding in the double-blind, randomized trial reported by Konstantinides et al. is that of the 118 patients treated with alteplase, only 1 had major bleeding and none had intracranial hemorrhage. These results are in sharp contrast to those reported by other groups. As Goldhaber notes in the accompanying Perspective,1 in the International Cooperative Pulmonary Embolism Registry, the incidence of intracranial hemorrhage in 304 patients receiving thrombolytic therapy was 3.0 percent. In a 1997 review that my colleagues and I reported,2 the incidence of intracranial hemorrhage in 559 patients treated with recombinant tissue plasminogen activator was 2.1 percent, and the incidence of fatal intracranial hemorrhage was 1.6 percent. In Levine's review of 227 patients with pulmonary embolism who were treated with recombinant tissue plasminogen activator, the incidence of major hemorrhage was 8.4 percent, and the incidence of fatal hemorrhage was 2.2 percent.3 The report by Konstantinides et al. is the only one in the literature in which the incidence of major bleeding with heparin alone was higher than the incidence with heparin plus a thrombolytic agent. Was this exceptionally low incidence of major bleeding in patients treated with alteplase due to chance, or was it due to more stringent contraindications to thrombolytic therapy? Given the fact that the bleeding complications of thrombolytic therapy are the main deterrent to its more widespread use in patients with pulmonary embolism, this becomes a critical question. What percentage of the patients screened for this study were excluded because of a contraindication to thrombolytic therapy?
3 ReferencesJames E. Dalen, M.D., M.P.H.
, Tucson, AZ 857181
Goldhaber SZ . Thrombolysis for pulmonary embolism. N Engl J Med 2002;347:1131-1132
Full Text | Web of Science | Medline2
Dalen JE ,Alpert JS ,Hirsch J . Thrombolytic therapy for pulmonary embolism: is it effective? Is it safe? When is it indicated? Arch Intern Med 1997;157:2550-2556
CrossRef | Web of Science | Medline3
Levine MN . Thrombolytic therapy for venous thromboembolism: complications and contraindications. Clin Chest Med 1995;16:321-328
Web of Science | Medline
To the Editor:
The report by Konstantinides et al. emphasizes that treatment with alteplase, given in conjunction with heparin, may improve the clinical course of patients with acute submassive pulmonary embolism. However, the grading of pulmonary embolism remains unclear. The definition cited in the article fails to differentiate massive from submassive pulmonary embolism1; presumably, submassive pulmonary embolism is characterized by right ventricular dysfunction or pulmonary hypertension without hemodynamic instability.
Pulmonary emboli have a wide spectrum of clinical severity and differ markedly in size and physiological effects. Right ventricular dysfunction appears to reflect a large thrombotic burden. We believe that Konstantinides et al. should have reported the results of lung scanning, spiral computed tomography (CT), or pulmonary angiography, since these studies provide quantification of the embolic load. Finally, how did the investigators ensure that right ventricular dysfunction or pulmonary hypertension did not predate the embolic event?
1 ReferencesAndrew E. Ajani, M.B., B.S.
Royal Melbourne Hospital, Melbourne 3105, AustraliaRon Waksman, M.D.
Washington Hospital Center, Washington, DC 20010
ron.waksman@medstar. net 1
Konstantinides S ,Geibel A ,Olschewski M , et al. Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry. Circulation 1997;96:882-888
Web of Science | Medline
Author/Editor Response
Ashton et al. and Gunn and Tierney question the validity of our combined end point, which includes the need for rescue thrombolysis. In our opinion, their concern is unjustified. In particular, the assumption that late thrombolysis was likely only in the placebo group is incorrect. Patients from both groups were eligible for and did receive emergency thrombolysis after the code had been broken, since, as shown in Figure 1 of our article, deterioration often occurred several hours or days after the administration of the study medication. We clearly stated in our article that mortality rates did not differ between the treatment groups. However, severe clinical or hemodynamic deterioration (as defined in the Methods section) requiring emergency thrombolysis is also an important adverse event and clinical end point. Since treatment with alteplase significantly reduced the risk of reaching this end point, we concluded that it can improve the outcome in patients with submassive pulmonary embolism. It would have been unacceptable to prohibit or ignore escalation of treatment in the study protocol.
As shown in Figure 2 of our article, the difference in activated partial-thromboplastin times during the first six hours was mostly due to high, supratherapeutic partial-thromboplastin values in the alteplase group rather than low values in the placebo group. Of the patients who reached the primary end point, only one patient in the alteplase group and four patients in the placebo group had subtherapeutic partial-thromboplastin times at six hours. All these patients had therapeutic values six hours later. The heparin regimen complied with medical statements of the American Heart Association at the time our study was designed.
The absence of intracranial hemorrhage in our study is similar to the findings of several trials of thrombolysis cited by Dalen.1 Although minor differences (in absolute numbers) between prospective trials involving patients with pulmonary embolism may be due to chance, in view of the relatively small numbers of patients included, the difference between the results of our trial and the results of previous registry studies2,3 underscores the importance of strict exclusion criteria based on the contraindications to thrombolysis.
In our study population, which was clearly defined in the Methods section of our article, submassive pulmonary embolism was characterized by right ventricular dysfunction or pulmonary hypertension without hemodynamic instability. The findings on lung scans or spiral CT scans were not reported because they have not been found to be directly correlated with right ventricular failure or with outcome. Finally, we have previously proposed the use of echocardiographic criteria to distinguish acute from subacute right ventricular pressure overload due to pulmonary embolism.4
4 ReferencesStavros Konstantinides, M.D.
Georg August University of Göttingen, D-37075 Göttingen, Germany
skonstan@med.uni-goettingen. de Wolfgang Kasper, M.D.
St. Josefs Hospital Wiesbaden, D-65189 Wiesbaden, Germany1
Dalen JE ,Alpert JS ,Hirsch J . Thrombolytic therapy for pulmonary embolism: is it effective? Is it safe? When is it indicated? Arch Intern Med 1997;157:2550-2556
CrossRef | Web of Science | Medline2
Goldhaber SZ ,Visani L ,De Rosa M . Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353:1386-1389
CrossRef | Web of Science | Medline3
Konstantinides S ,Geibel A ,Olschewski M , et al. Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry. Circulation 1997;96:882-888
Web of Science | Medline4
Kasper W ,Geibel A ,Tiede N , et al. Distinguishing between acute and subacute massive pulmonary embolism by conventional and Doppler echocardiography. Br Heart J 1993;70:352-356
CrossRef | Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
M.S. Levy, F. Spencer, J.S. Ginsberg, J.A.M. Anderson. (2008) Reading between the (Guidelines). Management of submassive pulmonary embolism in the first trimester of pregnancy. Thrombosis Research 121:5, 705-707
CrossRef2
David Jiménez, Carlos Escobar, David Martí, Gema Díaz, Rafael Vidal, Dolores Taboada, Javier Ortega, José Luis Moya, Vicencio Barrios, Antonio Sueiro. (2007) Valor pronóstico de la ecocardiografía transtorácica en pacientes estables hemodinámicamente con tromboembolia de pulmón aguda sintomática. Archivos de Bronconeumología 43:9, 490-494
CrossRef
