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Correspondence |

Low-Dose Tissue Plasminogen Activator in Pulmonary Embolism: Benefit Remains Unclear FREE TO VIEW

Shigeki Saito, MD; Basal Altaqi, MD; Francesco Simeone, MD; for the China Venous Thromboembolism (VTE) Study Group
Author and Funding Information

From the Department of Medicine (Dr Saito), Stanford University; and the Department of Medicine (Drs Altaqi and Simeone), Tulane University.

Correspondence to: Shigeki Saito, MD, Stanford University, 300 Pasteur Dr, H3143, Stanford, CA 94305; e-mail: shigekis@stanford.edu


Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2011 American College of Chest Physicians


Chest. 2011;139(2):479-480. doi:10.1378/chest.10-2333
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To the Editor:

We read the article in CHEST (February 2010) by Wang et al1 with great interest. However, we found several limitations. First, the authors tried to demonstrate the equivalency of low-dose and full-dose tissue plasminogen activator (tPA), although the superiority of full-dose tPA compared with anticoagulation in pulmonary embolism with right ventricular dysfunction is not firmly established, and its use remains controversial. The pulmonary embolism thrombolysis study, a large, ongoing European multicenter randomized controlled trial, will hopefully settle the controversy.

Second, the authors used a CT pulmonary angiography score as one of the surrogate end points. However, it is unclear whether this score is an adequate predictor of poor clinical outcome.2 To our knowledge, the correlation between this score and clinical outcome has never been validated in the setting of thrombolysis, and the use of surrogate end points in clinical research remains controversial.3

Third, the authors did not report the interobserver agreement (κ value) in their study. Previous studies have found a low interobserver agreement for the assessment of the surrogate end points chosen.2

Lastly, the authors used a difference of 10 points in CT pulmonary angiography score to calculate the sample size, without providing the rationale for using such a difference. It is not clear whether such a difference is clinically relevant. Moreover, they did not specify the margins of noninferiority and nonsuperiority, and the study seems grossly underpowered to test the equivalence.4 The authors could have chosen the outcomes and calculated the sample size based on the best (but limited) available evidence.5 In an equivalence trial, both participants and outcome measures should be similar to those in the trial(s) that established the efficacy of the reference treatment (100 mg tPA, in this case).5

Wang C, Zhai Z, Yang Y, et al; for the China Venous Thromboembolism (VTE) Study Group for the China Venous Thromboembolism (VTE) Study Group Efficacy and safety of low dose recombinant tissue-type plasminogen activator for the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial. Chest. 2010;1372:254-262. [CrossRef] [PubMed]
 
Araoz PA, Gotway MB, Harrington JR, Harmsen WS, Mandrekar JN. Pulmonary embolism: prognostic CT findings. Radiology. 2007;2423:889-897. [CrossRef] [PubMed]
 
Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996;1257:605-613. [PubMed]
 
Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJ. CONSORT Group CONSORT Group Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA. 2006;29510:1152-1160. [CrossRef] [PubMed]
 
Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002;34715:1143-1150. [CrossRef] [PubMed]
 

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References

Wang C, Zhai Z, Yang Y, et al; for the China Venous Thromboembolism (VTE) Study Group for the China Venous Thromboembolism (VTE) Study Group Efficacy and safety of low dose recombinant tissue-type plasminogen activator for the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial. Chest. 2010;1372:254-262. [CrossRef] [PubMed]
 
Araoz PA, Gotway MB, Harrington JR, Harmsen WS, Mandrekar JN. Pulmonary embolism: prognostic CT findings. Radiology. 2007;2423:889-897. [CrossRef] [PubMed]
 
Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996;1257:605-613. [PubMed]
 
Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJ. CONSORT Group CONSORT Group Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA. 2006;29510:1152-1160. [CrossRef] [PubMed]
 
Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002;34715:1143-1150. [CrossRef] [PubMed]
 
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