PULMONARY EMBOLISM MANAGEMENT Dr Bijilesh U Concurrently with

PULMONARY EMBOLISM MANAGEMENT Dr Bijilesh U

• Concurrently with the diagnosis of PE, prognostic assessment is required for risk stratification and therapeutic decision-making

Risk Stratification • Wide spectrum of illness ranging from mild to severe • Rapid and accurate risk stratification is of paramount importance • Appropriate care can range from prevention of recurrent PE with anticoagulation alone in low-risk patients to thrombolysis or embolectomy in high-risk patients

The three key components for risk stratification • Clinical evaluation • Assessment of right ventricular size and function • Analysis of cardiac biomarkers such as troponin, pro-BNP, and BNP

Clinical assessment of haemodynamic statu. S Hypotension and shock • Shock and hypotension are principal markers of high risk of early death in acute PE • 90 -day all-cause mortality rate – 52. 4% (95% CI, 43. 3– 62. 1%) - with SBP < 90 mm. Hg – 14. 7% (95% CI, 13. 3– 16. 2%) in normotensive patients • Post hoc analysis of ICOPER data • Systemic hypotension carry a slightly lower risk compared with shock (in-hospital all-cause mortality, 15. 2 vs. 24. 5%, respectively) • data from MAPPET registry

Markers of right ventricular dysfunction Echocardiography • A meta-analysis found more than a two-fold increased risk of PE-related mortality with echocardiographic signs of RV dysfunction • Patients with normal echo had an excellent outcome, with in hospital PE-mortality <1% • Also identify two specific markers, each indicating doubled mortality risk in PE – right-to-left shunt through a patent foramen ovale – presence of right heart thrombi

RV dysfunction RV dilation (apical 4 -chamber RV diameter divided by LV diameter > 0. 9) or RV systolic dysfunction on echo RV dilation (4 -chamber RV diameter/ LV diameter > 0. 9) on CT Elevation of BNP (> 90 pg/m. L) Elevation of N-terminal pro-BNP (> 500 pg/m. L); or ECG change (new complete or incomplete RBBB, anteroseptal ST elevation or depression or anteroseptal T-wave inversion) Circulation. 2011; 123: 1788 -1830

Brain natriuretic peptide (BNP) • Ventricular dysfunction is associated with increased myocardial stretch which leads to the release of BNP • Levels of BNP or N-terminal pro. BNP (NT-pro. BNP) reflect the severity of RVD and haemodynamic compromise • Kruger S, Merx MW, Graf J. Circulation 2003; 108: e 94–e 95 • High levels - related to worse outcome but PPV is low (12– 26%) • Low levels of BNP or NT-pro. BNP identify patients with a good prognosis regarding short-term mortality or a complicated clinical outcome (NPV 94– 100%)

Markers of myocardial injury Cardiac troponins • Myocardial injury in patients with PE can be detected by troponin T or I testing • Positive results are related to an intermediate risk of shortterm mortality in acute PE • Prognostic assessment based on signs of myocardial injury is limited by the lack of universally accepted criteria • Positive troponin T was related to an in-hospital mortality of 44%, compared with 3% for negative troponin T • [odds ratio 15. 2; 95% CI, 1. 2– 190. 4] • Giannitsis E et al. Independent prognostic value of cardiac troponin T in patients with confirmed pulmonary embolism. Circulation 2000; 102: 211– 217.

Myocardial necrosis • PPV of elevated troponin for PE-related early mortality was in range of 12– 44%, with very high NPV (99– 100%) • A recent meta-analysis confirmed that elevated troponin levels were associated with increased mortality in the subgroup of haemodynamically stable patients (OR, 5. 9; 95% CI, 2. 7– 12. 9) • Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis. Circulation 2007; 116: 427– 433. • Elevation of troponin I (>0. 4 ng/m. L) or • Elevation of troponin T (>0. 1 ng/m. L) Circulation. 2011; 123: 1788 -1830

New markers of myocardial injury Heart type fatty acid binding protein (H-FABP) • Early marker of myocardial injury • Reported to be superior to troponin or myoglobin measurements for risk stratification of PE on admission • H-FABP. 6 ng/m. L had a PPV and NPV for early PE-related mortality of 23– 37% and 96– 100%, respectively

• High-risk PE - shock or persistent arterial hypotension (defined as a SBP < 90 mm. Hg or a pressure drop of ≥ 40 mm. Hg for > 15 min) if not caused by new-onset arrhythmia, hypovolaemia or sepsis) • In the remaining normotensive patients with non-high-risk PE, the presence of markers of RV dysfunction and/or myocardial injury identify intermediate-risk PE • Haemodynamically stable patients without evidence of RVD or myocardial injury have low-risk PE

Additional riskfactors • Consideration of pre-existing patient-related factors may be useful in final risk stratification • Risk scores for prognostic stratification have been proposed

Pulmonary Embolism Severity Index - PESI ESC Guidelines European Heart Journal (2008)

Treatment Haemodynamic and respiratory support • Acute RV failure with resulting low systemic output is the leading cause of death in patients with high-risk PE • Therefore, supportive treatment is of vital importance in patients with PE and RV failure

Thrombolysis • First-line treatment in patients with high-risk PE presenting with cardiogenic shock and/or persistent arterial hypotension • Routine use of thrombolysis in non-high-risk patients is not recommended • But may be considered in selected patients with intermediaterisk PE and after consideration of conditions increasing the risk of bleeding • Should be not used in patients with low-risk PE

Approved thrombolytic regimens for pulmonary embolism ESC Guidelines European Heart Journal (2008) 29

Approved thrombolytic regimens for pulmonary embolism Reteplase • Double dose 10 -U IV bolus 30 min apart Tenecteplase • Weight-adjusted IV bolus over 5 s (30– 50 mg with a 5 -mg step every 10 kg from 60 to 90 kg)

• Overall, approximately 92% of patients can be classified as responders to thrombolysis based on clinical and echocardiographic improvement within the first 36 h • Thrombolysis can still be useful in patients who have had symptoms for 6– 14 days • Thrombolytic therapy carries a significant risk of bleeding • Randomized trials reveal a 13% cumulative rate of major bleeding and a 1. 8% rate of intracranial/fatal haemorrhage

Absolute contraindications • Haemorrhagic stroke or stroke of unknown origin at any time • Ischaemic stroke in preceding 6 months • Central nervous system damage or neoplasms • Recent major trauma/surgery/head injury (within preceding 3 weeks) • Gastrointestinal bleeding within the last month • Known bleeding Relative contraindications • Transient ischaemic attack in preceding 6 months • Oral anticoagulant therapy • Pregnancy or within 1 week post partum • Non-compressible punctures • Traumatic resuscitation • Refractory hypertension (systolic blood pressure >180 mm. Hg) • Advanced liver disease • Infective endocarditis • Active peptic ulcer

Surgical pulmonary embolectomy • Valuable therapeutic option in patients with highrisk PE in whom thrombolysis is absolutely contraindicated or has failed • Also in PE with Patent foramen ovale and intracardiac thrombi • In the past early mortality rates were high • In a more recent study, 47 patients underwent surgical embolectomy in a 4 -year period, with a 96% survival rate • Leacche M, J Thorac Cardiovasc Surg. 2005

Percutaneous catheter embolectomy and fragmentation • When thrombolysis is absolutely contraindicated or has failed or when emergency surgical thrombectomy is unavailable or contraindicated • Hybrid therapy - includes both catheter-based clot fragmentation and local thrombolysis is an emerging strategy • Goals of catheter-based therapy include – Rapidly reducing pulmonary artery pressure, RV strain, and pulmonary vascular resistance (PVR) – Increasing systemic perfusion; – Facilitating RV recovery

• There are 3 general categories – Aspiration thrombectomy – Thrombus fragmentation, – Rheolytic thrombectomy • Aspiration thrombectomy uses sustained suction applied to the catheter tip to secure and remove thrombus • Greenfield suction embolectomy catheter remains the only FDA approved device

• Thrombus fragmentation has been performed with balloon angioplasty, a pigtail rotational catheter, or a more advanced fragmentation device, Amplatze catheter • Rheolytic thrombectomy catheters include the Angio. Jet , Hydrolyser and Oasis catheters • Use a high-velocity saline jet to fragment adjacent thrombus by creating a Venturi effect

Recommendations for Catheter and Surgical Embolectomy • Reasonable for pts with massive PE and contraindications to fibrinolysis (Class IIa) • Reasonable for pts with massive PE who remain unstable after receiving fibrinolysis (Class IIa) • Either may be considered for submassive acute PE judged with clinical evidence of adverse prognosis (new hemodynamic instability, worsening respiratory failure, severe RV dysfunction, or major myocardial necrosis) (Class IIb) • Not recommended for low-risk PE or submassive acute PE with minor RV dysfunction, minor myocardial necrosis (Class III) • AHA guidelines, Circulation. 2011; 123: 1788 -1830

• In a systematic review comprising a total of 348 patients, clinical success with percutaneous therapy for acute massive PE was 81% – aspiration thrombectomy 81% – fragmentation 82% – rheolytic thrombectomy 75%) • Clinical success was 95% when combined with local infusion of thrombolytic agents – aspiration thrombectomy 100% – fragmentation 90% – rheolytic thrombectomy 91% • Skaf E, Catheter-tip embolectomy in the management of acute massive pulmonary embolism. Am J Cardiol. 2007

• In a retrospective report 51 patients with massive or submassive PE was treated with Angio. Jet rheolytic thrombectomy • (28% with shock, 16% with hypotension, and 57% with echocardiographic evidence of RV dysfunction) • Technical success was achieved in 92%, 8% experienced major bleeding, and in-hospital mortality was 16% • Chechi T, Rheolytic thrombectomy in patients with massive and submassive acute pulmonary embolism. Catheter Cardiovasc Interv. 2009; 73: 506 – 513.

Recommendations for initial anticoagulation for acute PE • Therapeutic anticoagulation with s/c LMWH, iv or s/c UFH with monitoring, unmonitored weight-based subcutaneous UFH, or subcutaneous fondaparinux should be given to patients with objectively confirmed PE and no contraindications to anticoagulation (Class I) • Therapeutic anticoagulation during the diagnostic workup should be given to patients with intermediate or high clinical probability of PE and no contraindications to anticoagulation (Class I) • AHA guidelines, Circulation. 2011; 123: 1788 -1830

Recommendations for initial anticoagulation for acute PE IV unfractionated heparin • Initial bolus 80 units/kg followed by 18 units/kg /h • Subsequent doses adjusted using a. PTT based nomogram • Maintain a. PTT between 1. 5 and 2. 5 times control • Measured 4– 6 h after the bolus injection and then 3 h after each dose adjustment • Once daily when the target therapeutic dose has been reached

Adjustment of intravenous unfractionated heparin dosage based on the activated partial thromboplastin time Raschke RA, Gollihare B, Peirce JC. The effectiveness of implementing the weight-based heparin nomogram as a practice guideline. Arch Intern Med 1996; 156: 1645– 1649

Low molecular weight heparins • Except for patients at high risk of bleeding and those with severe renal dysfunction, subcutaneous LMWH or fondaparinux rather than intravenous unfractionated heparin should be considered for initial treatment • LMWH cannot be recommended for high-risk PE , as such patients were excluded from randomized trials • Anti-factor Xa activity (anti-Xa) levels – considered in severe renal failure & pregnancy

Subcutaneous regimens of LMWH heparins and fondaparinux approved for pulmonary embolism

Recommendations for initial anticoagulation for acute PE • Begin warfarin (Coumadin) the same day as parenteral anticoagulation; delay is not advised • Continue parenteral anticoagulation for at least 5 days, even if the INR reaches 2. 0 earlier • Continue parenteral anticoagulation until the INR is at least 2. 0 for 24 hours or more

• Requirement for an initial course of heparin in addition to VKAs, compared with starting treatment with VKA therapy alone, was established in a randomized controlled study that reported a threefold higher rate of recurrent VTE in patients who received VKAs only

Fondaparinux • Valuable alternative to LMWH • Selective factor Xa inhibitor • Given subcutaneously at weight-adjusted doses without monitoring • Half-life of 15– 20 h - once-a-day administration • Platelet count monitoring is not needed • Contraindicated in severe renal failure with creatinine clearance < 20 ml/min

NEWER DRUGS 1. RIVAROXABAN -Direct Factor Xa inhibitor -Prophylaxis of VTE -Avoid if Ccr<15 ml 2. DABIGATRAN, bivalirudin, lepirudin, argatroban Direct thombin inhibitors

• A fixed-dose regimen of rivaroxaban alone was noninferior to standard therapy for the initial and long-term treatment of pulmonary embolism and had a potentially improved benefit– risk profile

• Dabigatran was effective in the extended treatment of venous thromboembolism and carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo

Therapeutic strategies ESC Guidelines European Heart Journal (2008)

Recommendations: acute treatment ESC Guidelines European Heart Journal (2008)

Optimal Duration of Anticoagulation CLINICAL SETTING RECOMMENDATION First provoked PE/proximal leg DVT First provoked upper extremity DVT or isolated calf DVT Second provoked VTE 3 to 6 months Third VTE Unprovoked PE/proximal leg DVT Indefinite duration Consider indefinite duration or until cancer is resolved Consider indefinite duration First unprovoked calf DVT 3 months Second unprovoked calf DVT Uncertain Cancer and VTE 3 months Uncertain

Risk Factors for Recurrent Venous Thromboembolism While anticoagulants are being taken • Increasing age • Immobilization • Cancer • Chronic obstructive pulmonary disease • Right ventricular enlargement or right ventricular dyskinesis After anticoagulants are discontinued • • • Male sex Overweight Presenting symptoms of PE rather than DVT Low levels of HDL-cholesterol Lack of leg vein recanalization on venous ultrasound examination

Venous filters • Filters are usually placed in the infrarenal portion of the inferior vena cava • Early complications - insertion site thrombosis, occur in 10% of patients • Late complications – Recurrent DVT (20%) – Post-thrombotic syndrome in 40% • Overall, occlusion of the vena cava affects approximately 22% of patients at 5 years and 33% at 9 years, regardless of the use and duration of anticoagulation • PREPIC randomized study. Circulation 2005; 112: 416– 422

Recommendations on IVC Filters in Acute PE • Confirmed acute PE with contraindications to anticoagulation or with active bleeding complication should receive an IVC filter (Class I) • Anticoagulation should be resumed in patients with an IVC filter once contraindications to anticoagulation or active bleeding complications have resolved (Class I) • For pts with recurrent acute PE despite anticoagulation, it is reasonable to place an IVC filter (Class IIa)

PREPIC Trial • Randomized 400 patients with proximal DVT at high risk for PE to receive UFH versus LMWH, with or without an IVC filter • Primary outcome was objectively documented PE at 8 years • IVC filters significantly reduced the incidence of recurrent PE • At 12 days (1. 1% versus 4. 8%, P< 0. 03) and at 8 years (6. 2% versus 15. 1%, P<0. 008) • But were associated with an increased incidence of recurrent DVT at 2 years (20. 8%versus 11. 6%, P<0. 02)

• No differences in major bleeding, postthrombotic chronic venous insufficiency, or death during the study period • In summary, the beneficial effects of IVC filters to prevent recurrent PE in patients with DVT at high risk for PE were offset by an increased incidence of recurrent DVT with no effect on overall mortality • Eight-year follow-up of patients with permanent vena cava filters in the preventionof pulmonary embolism: the PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) randomized study. Circulation 2005; 112: 416– 422

Pregnancy • Incidence of PE during pregnancy ranges between 0. 3 and 1 per 1000 deliveries • PE is the leading cause of pregnancy-related maternal death in developed countries • An accurate diagnosis is necessary, in pregnant women with a clinical suspicion of PE because a prolonged course of heparin is required • All diagnostic modalities, including CT scanning, may be used without significant risk to the fetus

• Upper limit with regard to the danger of injury to the fetus is considered to be 50 m. Sv (50 000 m. Gy) and all radiological tests fall well below thi s limit • Recent data on chest CT suggest that the radiation dose delivered to the fetus is lower than that of perfusion lung scintigraphy in the first or second trimester ESC Guidelines. European Heart Journal (2008)

D-dimer in pregnancy • Plasma D-dimer levels increase physiologically throughout pregnancy • A normal D-dimer value has the same exclusion value for PE in pregnant women as in other patients with suspected PE • An elevated D-dimer result should be followed by lower limb CUS since a positive result warrants anticoagulation treatment and makes thoracic imaging unnecessary

Treatment • Unfractionated heparin or Low molecular weight heparins are recommended in confirmed PE • Anti-xa monitoring may be considered with LMWH in women at extremes of body weight or with renal disease • VKAs are not recommended during the first and third trimesters • May be considered with caution in the second trimester • Anticoagulant treatment should be administered for at least 3 months after delivery

Malignancy • Patients with an idiopathic or unprovoked PE subsequently develop a cancer in about 10% of cases over 5– 10 years • Malignancy is a major predisposing factor for the development and recurrence of VTE • Risk of thrombosis in cancer is about four times higher than in the general population and the risk increases to about 6. 7 -fold in patients receiving chemotherapy • However, routine extensive screening for cancer in patients with a first episode of nonprovoked PE is not recommended

• Studies indicate that there is a good safety profile for the administration of LMWH to cancer patients • CLOT trial – (Randomized Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent VTE in Patients With Cancer) – use of dalteparin relative to oral anticoagulants was associated with improved survival • FAMOUS – (Fragmin Advanced Malignancy Outcome Study) – Also showed benefit in survival

• For patients with PE and cancer, LMWH should be considered for the first 3– 6 months • After this period, anticoagulant therapy with VKAs or LMWH should be continued indefinitely, or until the cancer is considered cured

Right heart thrombi • Right heart thrombi, particularly when mobile, i. e. in transit from the systemic veins, are associated with a significantly increased risk of early mortality in patients with acute PE • Immediate therapy is necessary, but optimal treatment is controversial in the absence of controlled trials • Thrombolysis and embolectomy are probably both effective whereas anticoagulation alone appears less effective

• In the ICOPER registry, thrombolytic treatment was the preferred option but the 14 -day mortality was above 20% • Surgical embolectomy seems a treatment of choice in right heart thrombi straddling the interatrial septum through the foramen ovale

Heparin-induced thrombocytopenia • HIT is a life-threatening immunological complication of heparin therapy • Monitoring of platelet counts in patients treated with heparin is important for the early detection of HIT • Ig. G antibodies bind to a heparin–platelet factor 4 complex • Occurs about 10 times more often with UFH than with LMWH • Suspect HIT when the platelet count decreases to less than 100, 000 or to less than 50% of baseline

• Typically occurs after 5 to 10 days of heparin exposure • Paradoxically fall in the platelet count, patients are at high risk of venous and arterial thromboembolic events • UFH or LMWH should be immediately discontinued, and platelets should not be transfused • A direct thrombin inhibitor such as argatroban, bivalirudin, or lepirudin should be used

Chronic thromboembolic pulmonary hypertension • CTEPH is a severe though rare consequence of PE • Pulmonary endarterectomy provides excellent results - firstline treatment • Perioperative mortality - 4% in patients with a preoperative PVR < 900 dyn s cm -5 and 20% with PVR >1200 dyn s cm -5 • Functional results are excellent and generally sustained over time, witha 3 -year survival rate of about 80%. • Drugs targeting the pulmonary circulation in patients in whom surgery is not feasible or has failed are currently being tested

Non-thrombotic pulmonary embolism • Due to a variety of embolic materials and result in a wide spectrum of clinical presentations, making the diagnosis difficult – – – Septic embolism Amniotic fluid embolism Fat embolism. Venous Air embolism Tumour embolism • With the exception of severe air , amniotic fluid and fat embolism, the haemodynamic consequences of nonthrombotic emboli are usually mild • Treatment is mostly supportive but may differ according to the type of embolic material and clinical severity

Summary • Evaluation of haemodynamic status, signs of RVD and myocardial injury and the assessment of additional patientrelated factors are useful for optimal risk stratification • Shock and hypotension are principal markers of high risk of early death in acute PE RV dysfunction is related to intermediate risk of short-term mortality in acute PE • • Myocardial injury in patients with PE can be detected by troponin T or I testing. Positive results are related to an intermediate risk of short-term mortality in acute PE

Summary • Thrombolytic therapy is the first-line treatment in patients with high-risk PE • Routine use of thrombolysis in non-high-risk patients is not recommended, but may be considered in selected patients with intermediate-risk PE • Should be not used in patients with low-risk PE • Pulmonary embolectomy is a valuable therapeutic option in patients with highrisk PE in whom thrombolysis is absolutely contraindicated or has failed

Summary • Catheter embolectomy may be considered as an alternative to surgical treatment in high-risk PE patients when thrombolysis is absolutely contraindicated or has failed • Anticoagulation should be initiated without delay in patients with confirmed PE and those with a high or intermediate clinical probability of PE while the diagnostic workup is still ongoing • Except for patients at high risk of bleeding and those with severe renal dysfunction, subcutaneous LMWH or fondaparinux rather then intravenous unfractionated heparin should be considered for initial treatment.

THANKS