Ver el código de «EBQ:PEITHO Trial»

{{JC info
| title= Fibrinolysis for patients with intermediate-risk pulmonary embolism
| abbreviation= PEITHO 
| expansion= Pulmonary Embolism Thrombolysis Trial
| published= 2014-04
| author= Meyer G. et al. 
| journal= NEJM
| year= 2014
| volume= 10
| issue= 370
| pages= 1402-1411
| pmid= 24716681
| fulltexturl= http://www.nejm.org/doi/full/10.1056/NEJMoa1302097
| pdfurl=http://theddx.org/papers/PEITHO.pdf
| status=Complete
}}
==Clinical Question==
'''Does thrombolysis with tenecteplase reduce mortality or hemodynamic collapse in patients with [[Pulmonary_Embolism_(PE)#Submassive|sub-massive PE]] at 7 days compared to placebo?'''

==Conclusion==
*'''Fibrinolytic therapy prevented hemodynamic decompensation but at the risk of increased hemorrhage and stroke'''

==Major Points== 
The Pulmonary Embolism Thrombolysis (PEITHO) trial evaluated a single-dose tenecteplase with heparin therapy for the treatment of “intermediate risk” acute pulmonary embolism. Intermediate risk was defined as patient with pulmonary embolism in addition to right ventricular dysfunction on imaging, and elevated cardiac biomarkers.  For the primary ''composite'' endpoint of death or hemodynamic deterioration within 7 days, 2.6% of patients in the immediate thrombolysis group met the outcome vs. 5.6% of patients in the usual treatment arm (OR 0.44, p=0.02).

Intermediate risk PE has often been used synonymously with [[Pulmonary_Embolism_(PE)#Submassive|submassive PE]] however a standard definition has not been universally accepted. The American Heart Association has maintained that for massive pulmonary embolism, thrombolysis with tPA is an effective treatment strategy.<ref>Jaff M. et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011 Apr 26;123(16):1788-830</ref>.  This trial addressed thrombolysis in patients who are hemodynamically stable but had moderate PE evidenced on CTA.  Commonly, the group termed, sub-massive PE includes patients with elevated troponin, BNP, or RV dysfunction on echocardiogram.. The standard of treatment for the [[Pulmonary_Embolism_(PE)#Submassive|sub-massive PE]] group has been unclear and thrombolysis has not been standard care for treatment, with most of these patients receiving heparin to decrease clot propagation while clot is slowly broken down<ref>Konstantinides S. Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry. Circulation 1997;96: 882e888</ref>

==Study Design==
*Multicenter, double-blind, placebo- controlled randomized trio in 76 centers in 13 countriesl<ref>The Steering Committee. Single-bolus tenecteplase plus heparin compared with heparin alone for normotensive patients with acute pulmonary embolism who have evidence of right ventricular dysfunction and myocardial injury: rationale and design of the Pulmonary Embolism Throm- bolysis (PEITHO) trial. Am Heart J 2012; 163(1):33.e1-38.e1.</ref>
*N=1,005 (506 patients Tenecteplase arm and 499 patients in placebo arm)
*Follow-up: 30 days
*Primary composite outcome: All-cause mortality or hemodynamic decompensation at 7 days
*Data analysis using intention-to-treat
==Population==
===Patient Demographics===
:''tenecteplase vs placebo''
*Age: 66.5 (tenecteplase) vs 65.8 (placebo)
*SBP:  130 mm Hg vs 131 mm Hg
*HR: 94 vs 92 bpm
*Chronic pulmonary disease: 26% vs 34 %
*Chronic Heart failure: 4.2% vs 5.2%
*Previous PE: 24.9% vs 29.5%
*Cancer 8.1% vs 6.4%
*Surgery or trauma in pas month: 6.1% vs 5.4%
*Immobilization: 10.9% vs 11.2%
*Estrogen use: 5.9% vs 6.6%
===Inclusion Criteria===
*Age 18 years or older
*Acute PE (first symptoms occurring 15 days or less before randomisation) confirmed by lung scan, or a positive spiral computed tomogram, or a positive pulmonary angiogram
*Right ventricular dysfunction confirmed by echocardiography or spiral computed tomography of the chest and a positive troponin I or T test<ref>http://clinicaltrials.gov/show/NCT00639743</ref>
===Exclusion Criteria===
*Haemodynamic collapse at presentation as defined below:<br />
**need for CPR
**SBP<90 for 15min
**SBP drop 40mmHg x 15min plus end organ hypoperfusion (cold ext, low UOP, AMS)
**need for pressors
*Known significant bleeding risk (anti-platelet use not an exclusion)
*Administration of thrombolytic agents within the previous 4 days
*Vena cava filter insertion or pulmonary thrombectomy within the previous 4 days
*Uncontrolled hypertension defined as systolic BP >180 mm Hg and/or diastolic BP >110 mm Hg at randomisation
*Treatment with an investigational drug under another study protocol in the previous 7 days or greater, according to local requirements
*Previous enrolment in this study
*Known hypersensitivity to tenecteplase, alteplase, unfractionated heparin, or to any of the excipients
*Pregnancy, lactation or parturition within the previous 30 days. Women of childbearing age must have a negative pregnancy test or use a medically accepted method of birth control
*Known coagulation disorder (including vitamin K antagonists)
*Any other condition that the investigator feels would place the patient at increased risk if the investigational therapy is initiated

==Interventions== 
*Both groups were initiated on unfractionated heparin (UFH) immediately after randomization with goal ptt 2.0-2.5x the upper limit of normal
*No other anticoagulant was allowed until 48 hours after randomization
===Tenecteplase Group===
*Tenecteplase 30-50 mg IV once over 5-10 seconds 
*UFH also administered
*Significant between-group difference of receiving LWMH or fondaparinux before randomization 
(p=0.02)

===Placebo Group===
*Also received UFH

==Outcomes==
===Primary Outcome===
*'''Primary outcome was all cause mortality or hemodynamic decompensation at 7 days
*Tenecteplase group: 2.6%
*Placebo group: 5.6%

*''Hemodynamic Decompensation''
**''SBP <90 mmHg ≥ 15 min''
**''Decrease in SBP ≥ 40 mmHg for ≥ 15min with end organ hypoperfusion or need for vasopressors''
===Secondary Outcomes=== 
'''All-cause mortality'''
*7 days: 1.2% vs. 1.8% (OR 0.65; 95% CI 0.23-1.85; P=0.42)
*30 days: 2.4% vs. 3.2% (OR 0.73; 95% CI 0.34-1.57; P=0.42)
===Subgroup analysis===
'''Hemodynamic decompensation at 7 days'''
*1.6% vs. 5.0% (OR 0.30; 95% CI 0.14-0.68; P=0.002; NNT 29)
'''Recurrent PE at 7 days'''
*0.2% vs. 1.0% (OR 0.20; 95% CI 0.02-1.68; P=0.12; NNT 125)

'''Bleeding at 7 days'''
*Minor bleeding: 32.6% vs. 8.6%
*Major bleeding: 11.5% vs. 2.4%
'''Stroke at 7 days'''
*2.4% vs. 0.2% (OR 12.10; 95% CI 1.57-93.39; P=0.003; NNH 45)
*Ischemic: 0.4% vs. 0%
*Hemorrhagic: 2.0% vs. 0.2%

==Criticisms & Further Discussion==
*Major bleeding occurred five times as frequent in the treatment arm
*Half of the deaths in the placebo arm were "sudden unexplained" or "other" compared with bleeding or stroke complications in the thrombolysis arm
*Not all placebo patients developing hemodynamic collapse received subsequent thrombolysis; likewise, almost half of those who received open-label thrombolysis had no hemodynamic collapse.
*Meta-analysis shows that patients with pulmonary embolism, including those who were hemodynamically stable with right ventricular dysfunction, thrombolytic therapy was associated with lower rates of all-cause mortality and increased risks of major bleeding and ICH.<ref>Chatterjee S. et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014 Jun 18;311(23):2414-21. PMID 24938564</ref> Second, in a subset of 1331 patients older than 65 years, thrombolysis was associated with a higher rate of major bleeding (12.93% vs 4.10%)<ref>Beckman JA. Thrombolytic therapy for pulmonary embolism. JAMA. 2014;311(23):2385–2386. doi:10.1001/jama.2014.5993.</ref>
*Meta-analysis of thrombolytics in PE found NNT=59 for all-cause mortality and NNH=79 for intracranial hemorrhage. Major bleeding was not significantly increased for patients age 65 or younger Odds ratio=1.25 <ref>Chatterjee, S et al. “Thrombolysis for Pulmonary Embolism and Risk of All-Cause Mortality, Major Bleeding, and Intracranial Hemorrhage: A Meta-analysis.” (2014) JAMA 311(23):2414-2421</ref>

==External Links==
*[http://www.emlitofnote.com/2014/04/a-positive-primary-outcome-for-peitho.html EMLitofNote.com]
*[http://emnerd.com/the-adventure-of-the-greek-interpreter/ EMNerd]
==See Also==
{{Thrombolysis Submassive PE Trials}}
==Funding==
*Funded by the Programme Hospitalier de Recherche Clinique in France and others; PEITHO EudraCT number, 2006-005328-18; ClinicalTrials.gov number, NCT00639743

==Sources==
<references/>

[[Category:EBQ]]