February 2015 Tucson Pulmonary Journal Club: Fibrinolysis for PE

Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402-11. [CrossRef] [PubMed]

The role of fibrinolytic therapy among patients with intermediate-risk pulmonary embolism (PE) is controversial (1). When right ventricular dysfunction and myocardial injury are associated with PE, there is an increased risk of adverse events (2). However, the risk of bleeding with fibrinolytic therapy has previously been thought to outweigh the benefits among patients without overt hemodynamic collapse.

The Pulmonary Embolism Thrombolysis (PEITHO) trial was a multi-center, double-blind, placebo-controlled randomized trial designed to investigate the efficacy and safety of single-bolus injection with tenecteplase plus heparin anticoagulation versus heparin anticoagulation alone among normotensive patients with intermediate risk PE (3). The study included 1005 adult patients who were randomized within fifteen days of symptom onset; randomization occurred when both right ventricular dysfunction (echocardiography or spiral computed tomography) and myocardial injury (troponin I or T) were present. All patients were followed for 30 days. The primary outcome was death or hemodynamic collapse within 7 days of randomization. Safety outcomes included major extra cranial and intracranial hemorrhage within 7 days.

Fibrinolytic therapy was associated with less frequent hemodynamic collapse or death within 7 days of treatment (2.6% vs 5.6%, p=0.02). The result was primarily driven by fewer instances of hemodynamic collapse in tenecteplase group (1.6% vs 5.0%, p=0.002). At 30 days, there was no difference in mortality from any cause between the tenecteplase and usual care groups, 2.5% versus 3.2%, respectively (p=0.42). However, tenecteplase therapy was associated with higher risk of major bleeding and stroke than usual care, 11.5% versus 2.4% (p<0.001) and 2.4% versus 0.2% (p=0.003), respectively. Subgroup analysis showed a trend towards increased bleeding in patients older than 75 years though this was not significant (p=0.09).

PEITHO is a relatively large, expensive, randomized controlled trial that provides little guidance on the optimal care of patients with intermediate risk PE. While improvement in the composite outcome of death or hemodynamic decompensation was significant (Odds Ratio 0.44, CI_95% 0.23-0.87), the benefit was primarily driven by less frequent hemodynamic compromise. Furthermore, any treatment benefit must be weighed against a substantially increased risk of major bleeding (Odds Ratio 5.55, CI_95% 2.3-13.39) or stroke (Odds Ratio 12.10, CI_95% 1.57-93.39). Given that follow-up is limited to 30 days and no patient-reported/patient-centered outcomes are available, it is difficult to provide patients or clinicians with the evidence they need to weigh the risks and benefits. Until better data are available, thrombolytic therapy for intermediate risk PE still remains weakly supported due to unclear efficacy and high risks of major bleeding or stroke, particularly among older patients.

Aarthi Ganesh MD, Christian Bime MD, and Joe Gerald PhD

University of Arizona

Tucson, AZ

References

1. Konstantinides S, Goldhaber SZ. Pulmonary embolism: risk assessment and management. Eur Heart J. 2012;33:3014-22. [CrossRef] [PubMed]
2. Konstantinides S. Acute pulmonary embolism. N Engl J Med. 2008;359:2804-13. [CrossRef] [PubMed]
3. Meyer G, Vicaut E, Danays T, et al; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402-11. [CrossRef] [PubMed] 

Reference as: Ganesh A, Bime C, Gerald J. February 2015 Tucson pulmonary journal club: fibrinolysis for PE. Southwest J Pulm Crit Care. 2015;10(2):97-8. doi: http://dx.doi.org/10.13175/swjpcc028-15 PDF

May 2012 Pulmonary Journal Club

EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366:1287-97. (Click here for abstract)

Oral vitamin K antagonists such as warfarin have been the mainstay of treatment in venous thromboembolism and pulmonary embolism since its approval in 1954. Clinicians can not only attest to its effectiveness but also the burden that patients face in maintaining a therapeutic level. In 2010 the EINSTEIN-PE investigators published its review on rivaroxaban in the treatment of venous thromboembolism (1). The results of this large 3449 pt trial were favorable showing non inferiority to vitamin K antagonists. This study now looks at rivaroxaban as a therapeutic alternative to vitamin K antagonists in the treatment of pulmonary embolism. The main advantage of rivaroxaban is a standard once daily dosing regimen without the need for blood monitoring.

The study was a large randomized open label trial performed at 263 sites over 38 countries between 2007–2011. Inclusion criteria were imaging confirmed symptomatic pulmonary embolism with or without deep vein thrombosis. Exclusion criteria were extensive, however they did allow for 1 single dose of a vitamin K antagonist, or enoxaparin, heparin, fondaparinux to be given for less than for 48 hours. This is certainly reasonable as it would be unethical to leave diagnosed pulmonary embolism untreated for 48 hours. 4833 patients were included in the study. 2413 patients were randomized to standard therapy with vitamin K antagonists while 2420 were assigned to receive rivaroxaban 15mg twice daily for 3 weeks then 20mg daily thereafter. The average treatment length was 9 months and there were statistically significant differences in patient demographics. The primary outcomes were rates of recurrent venous thromboembolism as well and major and minor bleeding.

This study set out to prove that rivaroxaban was not inferior to vitamin K .antagonists. It accomplished this goal. The results showed that there were no statistically significant differences in rates of recurrent venous thromboembolism, however, there were increased incidences of major bleeding episodes within the standard (vitamin K antagonist) group at 52 events vs. 26 events in the rivaroxaban  group (p=0.003).

Is rivaroxaban ready for prime time and will it replace warfarin as the new standard of care in the treatment of venous thromboembolic disease? The initial data certainly looks promising, although we need to proceed with caution given that this is a non reversible, non-dialyzable agent. Cost will be a major limiting factor as 1 month supply of rivaroxaban is estimated at $900 vs. $20 for warfarin. A cost-effectiveness analysis looking at laboratory fees and rates of readmission for bleeding events will most likely be needed. Further longitudinal studies extending beyond 1 year may also be needed to establish safety and efficacy. For now this medication offers promise that the treatment of venous thromboembolic disease is about to change.

Manoj Mathew, MD FCCP MCCM

Associate Editor, Pulmonary Journal Club

Reference

1. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363:2499-2510.

Reference as: Mathew M. May 2012 pulmonary journal club. Southwest J Pulm Crit Care 2012;4:180-1. (Click here for a PDF version of the journal club)