Submassive PE
Pulmonary Embolism Epidemiology: Incidence VTE: 100-200/100,000 = 3rd most frequent cardiovascular disease Symptomatic DVT complicated by PE = 40-50% Sudden fatal PE = 34% Intermediate-risk = 20% Mortality: High-risk: ~20% Intermediate risk: ~2-5% Low-risk ~1% Morbidity: Intermediate risk ~30% Risk Factors: Acute: surgery, trauma, pregnancy, burns, CVC, paralysis & immobility Chronic: age, smoking, obesity, OCP, hormone replacement, malignancy, CCF, Lupus-anticoagulant Genetic: deficiency of Protein C&S or AT3, FV Leiden mutation, hyperhomocysteinaemia
Pathophysiology
Classification 1.Massive PE: acute PE + obstructive shock (SBP<90) 2.Submassive PE: acute PE + RV dysfunction OR myocardial necrosis ECG: RV stain new RBBB, anteroseptal TwI, anterior STE or depression BNP >90 CT: RV diameter/lv diameter >0.9 TTE: RV diameter/lv diameter >0.9 or RVED diameter>30mm OR RV systolic dysfunction OR tricuspid systolic velocity >2.6 m/s 3.Non-massive PE: haemodynamically stable without objective evidence of RV dysfunction
Systemic Thrombolysis Biological Rationale: clot burden LV filling + RV dysfunction chronic pulmonary HTN Advantages: mortality + morbidity Adverse effects: ICH major bleeding risk of recurrent PE
Systemic Thrombolysis Pharmacodynamics: fibrinolytic agents accelerate clot lysis by converting clot bound plasmin to plasminogen which degrades the fibrin structure of the clot. rtpa Dose (2014 ESC guidelines): 0.9mg/kg (up to 100mg) -> 10% IV bolus + 90% infusion over 2hrs OR 0.6mg/kg over 15mins (max 50mg) Pharmacokinetics: >50% cleared by the liver within 5 minutes of infusion cessation, ~80% in 10mins
Systemic thrombolysis Indications: 1. Cardiac arrest + proven or suspected PE 2. High risk PE 3. Intermediate risk PE: less well established -> Consider monitoring and Rx if deteriorating with half dose. Can be performed as late as 14 days. Contraindications Absolute: Risk of ICH: Any prior ICH, structural cerebrovascular disease or malignant intracranial neoplasm, ischaemic CVA<3/12, recent spinal or intracranial surgery, recent TBI with radiographic evidence of brain injury or bony # Risk of uncontrollable bleeding: Aortic dissection, active bleeding Relative: HPC: Pregnancy, uncontrolled HTN, Traumatic or prolonged CPR PMHx: >75yrs, dementia or remote ischaemic CVA, Hx severe poorly controlled HTN, major surgery within 3 weeks or recent internal bleeding <1/12 Meds: current use of anticoagulation
Fibrinolysis should be considered in all adult patients with cardiac arrest with proven or suspected PE [weak recommendation, very low quality of evidence] If a fibrinolytic drug is given in these circumstances, consider performing CPR for at least 60-90min before termination of resuscitation attempts [Class A; Expert consensus opinion].
Wan et al (2004, Circulation): Systematic review (11 studies, n=748) comparing thrombolysis Vs anticoagulation alone High risk haemodynamically unstable PE: recurrent PE or death = 19% -> 9.4% (OR=0.45) 55%, NNT=10 Unselected PE: mortality = 9.6% -> 6.7% (OR = 0.67) major bleeding = 6.1% -> 9.1% (OR=1.42) non-major bleeding = 10% -> 22% (OR=2.63) Unselected PE - high risk PE: mortality = 5.3% -> 4.8% (OR=1.07)
TOPCOAT trial (2014, J. Thromb Haem): MRCT (n=83) in submassive PE: LMWH + full-dose TPA or placebo Adverse outcome @ 90 days (death, shock intubation, major bleeding, recurrent PE, poor functional capacity): 37% -> 15% with trial terminated early
PEITHO trial (2014) multi-centre RCT (n=1006) in intermediate risk PE (RV strain + TnI/T): anticoagulation + full-dose Tenectaplase (30mg - 50mg) or placebo Death or haemodynamic compensation: 5.6% -> 2.6% (p=0.02) 7 day haemodynamic decompensation: 5% -> 1.6% (p=0.002) 7 day mortality: 1.8 -> 1.2% (p=0.42) 30 day mortality: 3.2% -> 2.4% (p=0.42) Bleeding ICH: 0.2% -> 2.0% (p=0.003) Major Extracranial bleeding: 1.2% -> 6.3% (p<0.001) ISTH Major bleeding : 2.4% -> 11.5% Minor bleeding: 8.6% -> 32%
Follow-up at 28 of original PEITHO study sites (n=709) after 24 months (median reassessment = 37.8 months) Long-term Mortality & cause of death: ~98% Clinical assessment after 24 months: ~50% Echocardiographic assessment after 24 months: ~41%
PEITHO patients Inclusion Criteria: >18yrs Objectively confirmed PE with onset of symptoms <16 days + RV dysfunction confirmed by TTE or CT Myocardial injury confirmed by TnI/T Exclusion Criteria Haemodynamic decompensation at presentation Known significant bleeding risk (but not anti-plts) Uncontrolled HTN (BP>180/110) Pregnancy, lactation or parturition within 30 days Previous thrombolysis, vena cava filter or pulmonary thrombectomy within 4 days Known hypersensitivity to any of the agents used
Treatment Protocol 1. Anticoagulation: Immediate unfractionated heparin bolus + infusion targeting APTT x2-2.5 baseline OR other anticoagulation according to local practice no other anticoagulants <48hr 2. Thrombolysis Vs Placebo: administered over 5-10 seconds
Morbidity Assessment Persistent dyspnoea or functional limitation: Thrombolysis = 36% Vs Placebo = 30.1% (p=0.23) Morbidity Mild exertional dyspnoea: 87% & 90% NYHA class 3 or 4: 12 & 10.9% Peripheral oedema: 5.1% & 2.2% Other signs or symptoms of pulmonary HTN: <2% pre-syncope, syncope tactile RV impulse, JVP, accentuated or splitting 2nd HS, S3 or S4, hepatomegally or ascites
Critique Strengths: large double blinded multi-centre RCT first large study of long-term morbidity and mortality outcome in such a trial Weaknesses: Dosing of thrombolytics: 2% ICH is a high rate and full dose rtpa + full dose anticoagulation may be seen to be too aggressive in this group 30 day mortality from respiratory failure & recurrent PE Vs acute bleeding - PEITHO demonstrated 30 day mortality with placebo Robustness of long-term morbidity comparison: baseline assessment was not for pulmonary HTN and therefore treatment groups may have been significantly different. Robustness of long-term morbidity assessment: only 50% of the 703 patients selected were clinically assessed. Does this represent a selection bias by the patients themselves?
Assessment: High Risk Submassive PE Identifying patients at high risk of PEA arrest Unstable symptoms Severe dyspnoea or hypoxia Lack of cardiovascular reserve: syncope or presyncope Progressive sympathetic compensation: shock index (HR/SBP) >1, lactate >4 Looks terrible: pale, diaphoretic, impending doom Identifying patients at high mortality risk for respiratory failure & recurrent PE PMHx of conditions pre-disposing to pulmonary HTN: OSA, obesity, COPD, lung diseases Significant residual clot burden +/- proximal DVT Identifying patients at high risk for massive bleeding Management Alternatives to systemic thrombolysis IVC filter Catheter directed thrombolysis Pulmonary thrombectomy Pre-emptive Vs Rescue systemic thrombolysis Systematic review of studies demonstrates a non-significant 1.4% mortality benefit with pre-emptive thrombolysis (Nakamura, 2014)? safe -dose thrombolysis +/- fibrinogen levels to guide Rx? avoiding or delaying concommittent anticoagulation
MOPPETT trial (2013, Am. J. Cardiol.): single centre RCT (n=121) in moderate PE (clinical signs + radiologically defined clot burden) anticoagulation + 0.5mg/kg alteplase or placebo Results: Mortality + recurrent PE: 10% -> 1.6% (but neither end point significant independently) Acute pulmonary HTN: 57% -> 16% Hospital LOS: 4.9 days -> 2.2 days Chronic pulmonary HTN + recurrent PE @ 18 months: 63% -> 16% Major Bleeding: No major bleeding in either group