Efficacy and Safety of Half Dose Alteplase Added to Heparine, in Patients With Moderate Pulmonary Embolism

The primary aim of this study is to evaluate whether mid dose (safe dose) of Alteplase in addition to standard treatment with heparin (LMWH) in patients with pulmonary embolism (PE) at intermediate risk, it is effective to reduce:

* right ventricular dysfunction
* pulmonary hypertension 24 hours and 7 days after the treatment
* PE recurrence to 7days and 30 days after the treatment without increasing the incidence of bleeding intra-extracranial

The guidelines of the European Society of Cardiology (ESC2014) confirm the indication for pharmacological revascularization with thrombolysis only to cases of pulmonary embolism at high risk and thus hemodynamically unstable (class of recommendation I, level of evidence B), reserving the surgical or interventional procedures to cases where thrombolysis has failed or is contraindicated, while it remains controversial the role of thrombolysis in patients with pulmonary embolism at intermediate risk; the current state, in EP intermediate risk, the standard treatment involves the administration of low molecular weight heparin (LMWH), or fondaparinux (for 5-10 days followed by anticoagulation therapy with vitamin K antagonists) or alternatively the new anticoagulants oral (NAO). Although the results of the study PEITHO, recently published, confirm the indication for thrombolytic therapy for primary reperfusion in patients with embolism pulmonary high risk and provide element of reflection about the incidence of intracranial hemorrhage major, recent studies suggest that the thrombolysis with tPA to reduced dose (about half the dose that used in standard thrombolysis) in addition to anticoagulants (low molecular weight heparin) may reduce pulmonary hypertension (systolic artery pulmonary pressure\> 40 mmHg) and the incidence of recurrent PE. In this protocol, based on the study MOPETT and pharmacokinetic data available, it is used a "safe dose" (safe dose reduced) of alteplase which provides a intravenous (iv) bolus loading dose of 10 mg in 1 min, followed by intravenous infusion 40 mg within two hours (for patients weighing \<50 kg loading dose iv bolus of 0.5 mg in 1 min, followed by iv infusion of 40 mg within two hours).

After treatment with alteplase, the heparin therapy will be resumed when aPTT values are less than twice the upper limit of normal; the infusion will be adjusted to maintain aPTT between 50-70 seconds (1.5 to 2.5 times the reference value), and for safety reasons are excluded patients\> 65 -70 years (increased risk of bleeding complications related age and comorbidities).

Eligibility Criteria:
Inclusion Criteria:

1. pulmonary embolism at intermediate risk as defined by the Guidelines ESC2014\[ documented pulmonary CT angiography\]
2. pulmonary hypertension (systolic pulmonary pressure greater or equal to 40 mm Hg) \[documented echocardiogram presence of thrombotic material in the right-sided\]
3. disfunction Ventricular right confirmed by echocardiogram or TC chest:

   * dilation of the right sections (\> 30 mm in parasternal or relationship right ventricle/left ventricle \> 1)
   * paradoxical movement of the interventricular septum
   * TAPSE reduced (Tricuspid Annular Plane Systolic Excursion)
   * tricuspid regurgitation with gradient VD/AD\> 30 mmHg, in the absence of right ventricular hypertrophy, McConnell sign (apical segment of the free wall of the right ventricle normalKinetic or hyperkinetic than a hypokinesia or akinesia of the remaining parts of the right ventricular wall),
4. myocardial damage confirmed with:

   * Troponin I or T positive
   * higt value of the biomarkers of myocardial damage : BNP or NTproBNP
5. informed consent

Exclusion Criteria:

1. age \<18 years and\> 65 years
2. HASBLED score ≥ 3 (23)
3. intracranial tumors
4. ischemic stroke within 2 months
5. surgery neurological within 1 month and surgery within 10 days
6. trauma within 15 days
7. hypotension to hospitalization (systemic blood pressure \<90 mmHg)
8. uncontrolled hypertension (SBP\> 180mmHg and PAD\> 110mmHg)
9. clotting disorders
10. thrombocytopenia (\<100.000)
11. platelet counts below 100 × 109 /L severe thrombocytopenia (platelet count \<50.000 ptl / mm3)
12. liver failure
13. kidney failure
14. gastrointestinal bleeding within 10 days
15. pregnancy or childbirth within 30 days
16. contraindications to the use of thrombolytics
17. contraindications to the use of low molecular weight heparin (enoxaparin)
18. anticoagulation therapy started more than 8 hours
19. COPD
20. endocarditis
21. severe obesity