Half the Dosage, Similar Efficacy, Less Bleeding

The standard dose of recombinant tissue-type plasminogen activator (rt-PA; alteplase) for pulmonary embolism (PE) treatment is 100 mg. In this issue of CHEST (see page 254), Wang and colleagues,1Wang C Zhai Z Yang Y for the China Venous Thromboembolism (VTE) Study Group et al.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; 137: 254-262Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar reporting a multicenter clinical trial from China, compare that dose with a dose of 50 mg. They conclude that the efficacy of 50 mg rt-PA was similar, and for patients weighing <65 kg with BMI <25, bleeding was reduced. Their recommendation to use 50 mg for patients <65 kg appears solidly grounded, but uptake should be cautious, for the usual reasons. Starting with the observation that half-dose (50 mg) rt-PA showed superior efficacy and similar safety to standard-dosage urokinase for establishing coronary artery patency in patients with acute myocardial infarction,2Ross AM Gao R Coyne KS TUCC Investigators et al.A randomized trial confirming the efficacy of reduced dose recombinant tissue plasminogen activator in a Chinese myocardial infarction population and demonstrating superiority to usual dose urokinase: the TUCC trial.Am Heart J. 2001; 142: 244-247Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Wang and colleagues1Wang C Zhai Z Yang Y for the China Venous Thromboembolism (VTE) Study Group et al.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; 137: 254-262Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar randomized patients with acute PE to receive either 50 or 100 mg IV and analyzed 24-h efficacy outcomes: echocardiographic right ventricular and pulmonary vascular imaging improvement. At day 14, they reevaluated these outcomes and also counted recurrent thromboembolic events, deaths, and bleeding events. They found similar efficacy and a trend overall (P =.08) toward less bleeding with the lower dose. Why might this report be less than 100% convincing to administer 50 mg IV rt-PA in lower body weight patients? There are several reasons, among them the “no difference” efficacy conclusion. Although the fraction of patients in each group with improved imaging at 24 h was similar (84%), imaging showed deterioration in 4% of 100 mg recipients but 11% of 50 mg recipients (P = .28). A glass-half-empty skeptic might reason that worsening (not improvement) is the imaging outcome of greatest importance and that a larger number of patients is required to relieve concern about that trend. Although one-third had hemodynamic compromise, the remaining two-thirds of the enrolled patients had only anatomic “severe” PE; maybe that last two-thirds did not need thrombolysis at all, and attentive anticoagulation would have sufficed. Capable investigators such as Wang et al1Wang C Zhai Z Yang Y for the China Venous Thromboembolism (VTE) Study Group et al.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; 137: 254-262Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar can find themselves on this type of thin ice whenever they do not enroll a placebo group (in this study, that double-blinded placebo group would have received anticoagulation only) and fail to find statistical superiority of either active treatment. The authors explain that in their medical culture in China, severe anatomic obstruction (not merely hypotension) warrants thrombolysis in the absence of a contraindication, a fair explanation but one that might leave a reader wondering if the results are robust enough to warrant using the 50-mg dosage. For this concern, a little historical perspective is useful. The key study3Goldhaber SZ Kessler CM Heit J et al.Randomised controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism.Lancet. 1988; 2: 293-298Abstract PubMed Scopus (301) Google Scholar that led to rt-PA approval for PE treatment in the United States had merely 22 patients in each group (rt-PA vs urokinase). These patients were hemodynamically stable and the outcome proving superiority of rt-PA relied upon repeat pulmonary angiography imaging just 2 h after the respective thrombolytic infusions—when only 2/24 of the 24-h approved urokinase dose had been given. Reperfusion improvement at 24 h from the two regimens was identical, the study reported. To become an established US Food and Drug Administration (FDA)-approved therapy for PE at the 100-mg dosage, rt-PA proved superiority for a surrogate outcome against a homeopathic dose of urokinase. It not only failed to slay Goliath, it barely nicked his shadow. The current study from China is strengthened by biologic plausibility. Refining and reducing dosages of anticoagulant and fibrinolytic drugs has a long and respected history. Unfractionated heparin, earlier given by q4h IV boluses, is now recommended by American College of Chest Physicians guidelines to be given in any of four very different ways: by IV weight-based dosing or a fixed number of units titrated to an activated partial thromboplastin time result, or by titrated or untitrated subcutaneous injection.4Kearon C Kahn SR Agnelli G Goldhaber S Raskob GE Comerota AJ American College of Chest Physicians Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition).Chest. 2008; 133: 454S-545SAbstract Full Text Full Text PDF PubMed Scopus (1860) Google Scholar Chronic warfarin dosing after thromboembolism can be targeted to an INR of 2 to 34 or, in some circumstances, 1.6 to 2.0.4Kearon C Kahn SR Agnelli G Goldhaber S Raskob GE Comerota AJ American College of Chest Physicians Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition).Chest. 2008; 133: 454S-545SAbstract Full Text Full Text PDF PubMed Scopus (1860) Google Scholar rt-PA itself was tested as a reduced-dose bolus before a phase 3 trial was stopped for an excessive death rate in the bolus group.5Goldhaber SZ Agnelli G Levine MN The Bolus Alteplase Pulmonary Embolism Group Reduced dose bolus alteplase vs conventional alteplase infusion for pulmonary embolism thrombolysis. An international multicenter randomized trial.Chest. 1994; 106: 718-724Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar An expert on the anticoagulant lepirudin for treatment of heparin-induced thrombocytopenia has repeatedly written that the approved, labeled dose is too high and should be reduced.6Lubenow N Eichler P Lietz T Greinacher A HIT Investigators Group Lepirudin in patients with heparin-induced thrombocytopenia—results of the third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2, and HAT-3.J Thromb Haemost. 2005; 3: 2428-2436Crossref PubMed Scopus (199) Google Scholar, 7Greinacher A Heparin-induced thrombocytopenia.J Thromb Haemost. 2009; 7: 9-12Crossref PubMed Scopus (112) Google Scholar The “standard dose” of drugs often proves to be wrong for some patients because of side effects. Drug dosages selected for studies aimed at FDA approval are intended to be high enough to show efficacy with, it is hoped, a safety margin. When the lead authors of a landmark study of steroid treatment of COPD exacerbation were challenged on why the protocol used such a high steroid dosage (hospital stays were shortened but subsequent admission days were increased), they answered, “We chose the highest dose…because we did not want post hoc criticism about inadequate doses if the trial had a negative result.”8Niewoehner DE Erbland M Collins D Glucocorticoids for chronic obstructive pulmonary disease.N Engl J Med. 1999; 341: 1772-1773Google Scholar rt-PA at 100 mg for PE was likely established with similar, clinically sound logic. But it need not stand as the last word. There could be a concern regarding generalizability to patients from non-Asian ethnic groups relating to a previous hypothesis2Ross AM Gao R Coyne KS TUCC Investigators et al.A randomized trial confirming the efficacy of reduced dose recombinant tissue plasminogen activator in a Chinese myocardial infarction population and demonstrating superiority to usual dose urokinase: the TUCC trial.Am Heart J. 2001; 142: 244-247Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar that there are genetically determined metabolic process differences in Asians that favor effective thrombolysis with a lower dosage of administered thrombolytic. However, the evidence assembled supporting this assertion2Ross AM Gao R Coyne KS TUCC Investigators et al.A randomized trial confirming the efficacy of reduced dose recombinant tissue plasminogen activator in a Chinese myocardial infarction population and demonstrating superiority to usual dose urokinase: the TUCC trial.Am Heart J. 2001; 142: 244-247Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar is weak. Moreover, in their post hoc search for an explanation of their safety findings, Wang and colleagues1Wang C Zhai Z Yang Y for the China Venous Thromboembolism (VTE) Study Group et al.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; 137: 254-262Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar provide support within their entirely Asian population that it was lower body weight that was associated with lower bleeding risk. Risk of hemorrhage is the major reason that only 2.4% of discharged patients with PE received a thrombolytic drug in a recent survey of Pennsylvania hospitals.9Ibrahim SA Stone RA Obrosky DS Geng M Fine MJ Aujesky D Thrombolytic therapy and mortality in patients with acute pulmonary embolism.Arch Intern Med. 2008; 168: 2183-2190Crossref PubMed Scopus (32) Google Scholar Among the thrombolysed patients, major bleeding occurred in 5.3% and was associated with a 54% mortality rate. A metaanalysis,10Wan S Quinlan DJ Agnelli G Eikelboom JW Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials.Circulation. 2004; 110: 744-749Crossref PubMed Scopus (513) Google Scholar influential registry report,11Goldhaber SZ Visani L De Rosa M Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER).Lancet. 1999; 353: 1386-1389Abstract Full Text Full Text PDF PubMed Scopus (2352) Google Scholar and other reviews12Dalen JE Alpert JS Hirsh J Thrombolytic therapy for pulmonary embolism: is it effective? Is it safe? When is it indicated?.Arch Intern Med. 1997; 157: 2550-2556Crossref PubMed Google Scholar, 13Carlbom DJ Davidson BL Pulmonary embolism in the critically ill.Chest. 2007; 132: 313-324Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar seem to concur that thrombolytic drugs can save lives but bleeding, particularly intracranial bleeding (1%–2%) should limit their use. Dose reduction, as tested by Wang et al,1Wang C Zhai Z Yang Y for the China Venous Thromboembolism (VTE) Study Group et al.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; 137: 254-262Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar could be a safer way to give life-saving rt-PA to many patients. Physicians should consider using Wang and colleagues' reduced rt-PA dose regimen in lower body weight patients with PE with hemodynamic compromise or another indication for thrombolysis. As other peer-reviewed studies have reported,14Konstantinides S Geibel A Heusel G Heinrich F Kasper W 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; 347: 1143-1150Crossref PubMed Scopus (874) Google Scholar, 15Meneveau N Sèronde MF Blonde MC et al.Management of unsuccessful thrombolysis in acute massive pulmonary embolism.Chest. 2006; 129: 1043-1050Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar efficacy failure might be addressed by re-treatment, with the same 50 mg or the approved 100-mg dose. Wang and colleagues' careful new look at rt-PA for thrombolysis is welcome. Although the results are not definitive, these data provide useful guidance that can favorably change practice. Efficacy and Safety of Low Dose Recombinant Tissue-Type Plasminogen Activator for the Treatment of Acute Pulmonary Thromboembolism: A Randomized, Multicenter, Controlled TrialCHESTVol. 137Issue 2PreviewOptimal dosing of the recombinant tissue-type plasminogen activator (rt-PA) is important in treating pulmonary thromboembolism (PTE). The aim of this study was to compare the efficacy and safety of a 50 mg/2 h rt-PA regimen with a 100 mg/2 h rt-PA regimen in patients with acute PTE. Full-Text PDF