Pulmonary Embolism: Current Concepts in Diagnosis and Management

1. Pulmonary Embolism: Current Concepts in Diagnosis and Management Gregory Piazza, MD July 26, 2005

2. Objectives • To examine the state-of-the-art in the evaluation of patients with suspected pulmonary embolism (PE). • To review the recent advances in risk stratification of patients with PE. • To highlight current approaches to the treatment of PE.

3. Spectrum of Disease • A variety of clinical syndromes may be seen: • Normotensive with normal RV function • Normotensive with RV dysfunction (submassive PE) • Cardiogenic shock (massive PE) • Cardiac arrest (massive PE)

4. Epidemiology • The incidence of PE in the U.S. is 1 per 1000 per year. • Only 1 out of every 3 cases of venous thromboembolism (VTE) is diagnosed. • With approximately 450,000 cases detected per year, a staggering 900,000 VTE cases may go unrecognized annually. • In the Olmsted County registry, 30-day mortality after PE or DVT has been reported as high as 28%. • The International Cooperative Pulmonary Embolism Registry (ICOPER) estimates a 3-month mortality of 17.4%. • These data suggest PE is possibly as deadly as acute myocardial infarction. Lancet 2004; 363:1295-1305 Arch Intern Med 1999;159:445-453 Lancet 1999;353:1386-1389 Circulation 2003;108:2726-2729

5. Case: Patient No. 1 • A 57 year old female with history of hypertension, diabetes, and asthma presents with acute onset right-sided chest pain and dyspnea. • She is currently taking lisinopril, metformin, albuterol, and estrogen with progesterone. • She smokes half a pack per day. • On exam, she is tachycardic, tachypneic, obese and anxious-appearing, with an oxygen saturation of 93% on RA. She has mild left lower extremity pitting edema.

6. Case: Patient No. 1 How should this patient be worked up?

7. History: Dyspnea (most frequent symptom) Pleuritic chest pain Cough Hemoptysis Syncope Physical Exam: Tachypnea (most frequent sign) Anxious appearance Tachycardia Fever Elevated JVD (most specific sign) Loud P2 Tricuspid regurgitation Paradoxical bradycardia The History and Physical

8. Arterial blood gases Electrocardiography Chest X-ray Plasma D-dimer Lower extremity ultrasound Echocardiography Ventilation-perfusion lung scanning Spiral chest CT Magnetic resonance (MR) angiography Contrast pulmonary angiography The Diagnostic Armamentarium “Everything you can do is not everything you should do.”

9. Electrocardiography Common electrocardiographic findings: • Sinus tachycardia • iRBBB/RBBB • RAD • S in I,L > 1.5mm • Q waves in III,F but not in II • TWI in III,F or V1-V4 • S1Q3T3 • Qr pattern in V1 Circulation 2002;106:459

10. Chest X-ray • Chest X-ray serves an important role in formulation of clinical suspicion for PE and may help suggest alternative pathology. • A recent review noted the most common chest X-ray interpretations: - cardiomegaly (27%) - normal (24%) - pleural effusion (23%) - elevated hemidiaphragm (20%) - pulmonary artery enlargement (19%) - atelectasis (18%) - pulmonary infiltrate (17%) Chest 2000;118(1):33-8

11. Plasma D-dimer • D-dimers are non-specific markers of ineffective endogenous fibrinolysis and may be elevated in many conditions, especially among inpatients. • A recent evaluation of D-dimer ELISA in a high-volume ED revealed a sensitivity of 96.4% and NPV of 99.6%. • The D-dimer ELISA alone can exclude PE in up to 30% of patients without further costly tests. • There is currently inadequate evidence to stop the evaluation for PE in patients with high clinical suspicion and normal D-dimer levels. • Qualitative latex agglutination assays (SimpliRED) lack the NPV to safely exclude PE. Ann Intern Med 2004;140:589-602 J Am Coll Cardiol 2002;40:1475-78 Ann Emerg Med 2002;39:144-52

12. Ventilation Perfusion (V/Q) Scan • V/Q scans are no longer the initial test of choice in the PE work-up. • Lung scanning is reserved for patients with renal failure, anaphylaxis to contrast, or pregnancy. • V/Q scans provide definitive information less than 50% of the time. • Normal V/Q scans practically exclude the possibility of PE while high-probability scans in the right setting guarantee the diagnosis. • However, the majority of scans fall into the intermediate or indeterminate range requiring further testing.

13. Chest CT Scan • Spiral chest CT is now the first choice for imaging PE. • The sensitivity of chest CT is highest in the proximal pulmonary arteries. • Early generation (“single-detector”) scanners are prone to miss small segmental or large subsegmental PE and have a sensitivity of approximately 70%. • Third generation “multi-detector” scanners have yielded a 40% increased detection rate for subsegmental PE and a 70% decrease in indeterminate studies. Sensitivity has improved to over 90%. • Chest CT provides information regarding the condition of the RV as well as conditions that mimic PE such as pneumonia. • PIOPED II should provide the most thorough analysis of the efficacy of chest CT to date. Ann Intern Med 2001;217:447-455 Radiology 2002;222:483-490

14. Echocardiography • Transthoracic echocardiography is insensitive in screening for PE but plays an important role in risk stratification based on the findings of RV dysfunction. • Transesophageal echocardiography (TEE) has the potential to diagnose pulmonary embolism by direct visualization. • TEE provides information about the extent and surgical accessibility of the PE if open embolectomy is considered. • TEE provides excellent visualization of main PA and right PA until it divides into lobar arteries. • In sudden cardiac compromise or PEA arrest, TEE may be a quick and effective method for diagnosing massive PE. Arch Intern Med 2000;160(10):1529-35

15. Contrast Pulmonary Angiography • Contrast angiography is indicated in the PE work-up when initial studies such as spiral CT or V/Q scan are nondiagnostic and clinical suspicion remains high. • Pulmonary angiography is being utilized with declining frequency and the number of experienced radiologists is decreasing. • Contrast angiography is an invasive study with the potential for significant morbidity and mortality. Circulation 1992;85(2):462-68

16. History and Physical Eval. clinical likelihood Patient in ED Electrocardiogram Chest radiograph Inpatient or high prob. D-dimer Normal High V/Q if dye allergy or renal insufficiency Chest CT No PE Normal Positive Equivocal Normal Ultrasonography Positive Negative No PE Treat for PE Consider PA-gram No PE An Integrated Approach Lancet 2004;363:1295-1305

17. Case: Patient No. 2 • A 67 year old male with history of CAD, HTN, and prostate cancer presents with acute onset dyspnea, lightheadedness, and dull chest pressure. • He is currently taking metoprolol, lisinopril, and aspirin. • On exam, he is tachycardic, tachypneic, hypoxic, but normotensive. He has elevated neck veins and new lower extremity edema. • His EKG reveals sinus tachycardia. • His chest X-ray is read as “no pneumonia, no CHF.” • Because of high clinical suspicion for PE, he undergoes chest CT.

18. Case: Patient No. 2 • The patient is started on a weight-based protocol of intravenous unfractionated heparin and admitted to a telemetry floor. • That evening, the patient’s roommate calls the nurses station to report that the patient has “slumped over in his chair.” • The patient is found unresponsive and a code is called. • The patient is found to be in pulseless electrical activity (PEA) and expires after resuscitative efforts are unsuccessful.

19. Case: Patient No. 2 Did we see this coming?

20. Risk Stratification Risk Stratification Tools: • History and physical • Clinical prognostic scores • Cardiac biomarkers including cardiac troponin and brain-type natriuretic peptide (BNP) • Chest CT • Echocardiography

21. ICOPER reported several independent clinical predictors of increased mortality at 3 months. History and Physical Lancet 1999;353:1386-9

22. Cardiac Biomarkers • Cardiac troponins and BNP have been extensively studied in the evaluation of patients with acute PE. • Cardiac troponins and BNP accurately identify low-risk PE patients with negative predictive values for in-hospital death ranging from 97 to 100%. • Patients presenting with acute PE and elevated cardiac biomarkers should undergo transthoracic echocardiography to assess RV function. • In patients with acute PE and normal levels of cardiac biomarkers, echocardiography is not routinely required as RV function will most often be normal. Circulation 2003;108:2191-2194

23. ↑ PVR ↑ RV pressure RV micro-infarction ↑ RV shear stress Myofibril degradation ↑ Natriuretic peptide mRNA ↑ Troponins ↑ BNP Cardiac Biomarkers Circulation 2003;108:2191-2194

24. No shock Shock BNP ↓ Troponin ↓ BNP ↑ Troponin ↑ Echocardiography No RV dysfunction RV dysfunction Anticoagulation alone Consider thrombolysis or embolectomy Cardiac Biomarkers Circulation 2003;108:2191-2194

25. Chest CT Scan • Although chest CT is used primarily for the diagnosis of PE, right ventricular dilatation may also be observed. • In a recent study, a ratio of RV dimension to LV dimension > 0.9 on a reconstructed 4 chamber view was an independent predictor of adverse events (OR 4.02, 95%CI 1.06-15.19; p = 0.041) when adjusted for age, obesity, cancer, and recent surgery. Circulation 2004;110:3276-3280

26. Echocardiography is very sensitive in identifying RV dysfunction in PE. RV dysfunction has proven to be one of the strongest predictors of adverse outcomes and recurrent PE. Typical findings in PE include: RV dilatation Moderate to severe RV free wall hypokinesis with apical sparing (McConnell Sign) Paradoxical interventricular septal motion TR/Pulmonary HTN Loss of respiratory-phasic changes in IVC Decrease in the difference between LV area during diastole and systole (marker of cardiogenic shock) Echocardiography Ann Intern Med 2002;136:691-700 Crit Pathways in Cardiol 2003;2:247-265

27. Case: Patient No. 3 • A 44 year old female with no significant past medical history presents with sudden onset dyspnea and chest discomfort. • She also notes left lower extremity swelling and pain for the past three days. • On physical exam, she is normotensive but mildly tachypneic, tachycardic, and hypoxic. She has moderate pitting edema of the left leg. • Because of her symptoms and exam, a chest CT is performed and reveals bilateral PE.

28. Case: Patient No. 3 How should we manage this patient?

29. Primary therapy: Thrombolysis Open surgical embolectomy Catheter-assisted embolectomy Secondary therapy: IV unfractionated heparin Low-molecular weight heparin (LMWH) Fondaparinux Warfarin IVC filter Primary v. Secondary Therapy

30. Management • In patients with massive PE, primary therapy with thrombolytics is considered a lifesaving intervention. • Surgical or catheter-assisted embolectomy may be considered for massive PE if thrombolysis is contraindicated. • For submassive PE, thrombolysis remains controversial as no mortality benefit has been shown in this patient population. • However, MAPPET-3 demonstrated a reduction in need for escalation of therapy in patients receiving up-front t-PA (alteplase) for submassive PE. • Normotensive patients with normal RV function are considered low-risk and receive standard anticoagulation. J Thromb Thrombolysis 1995;2:227-229 N Engl J Med 2002;347:1143-1150

31. Low Molecular Weight Heparin • LMWHs have a longer half-life, better bioavailability, and more predictable dose-response. • In clinical trials, enoxaparin, reviparin, and tinzaparin have all been proven as safe and effective as unfractionated heparin in “bridging” patients with PE to oral anticoagulation. • LMWH is renally-cleared while unfractionated heparin is largely cleared by the liver. • The PTT should not be used to monitor/adjust LMWH. Instead, an anti-Xa level should be checked 4-6 hours after the 2nd/3rd dose. • Anti-Xa levels may be required in patients with renal insufficiency, obesity (>110kg), pregnancy, or unexpected bleeding or thromboembolism despite standard LMWH dosing. N Engl J Med 1997;337:657-662 N Engl J Med 1997;337:663-669 Ann Intern Med 2001;134(3):191-202

32. Warfarin • Warfarin is very effective in preventing recurrent VTE but carries a significant risk of bleeding. • Loading doses of greater than 5 mg daily remain controversial although a recent study showed 10 mg initiation safely allowed for more rapid achievement of a therapeutic INR. • Patients taking warfarin potentiators such as quinolones, anti-platelet agents, and amiodarone are at higher risk for bleeding. Ann Intern Med 2003;138:714-719

33. Cumulative risk of recurrent venous thromboembolism Duration of Anticoagulation: PREVENT • The multicenter NIH-sponsored PREVENT trial of 508 patients with idiopathic VTE evaluated indefinite low intensity warfarin (INR 1.5-2.0) versus placebo. • The trial was terminated early after a mean follow-up of 2.1 years. • A 2/3 reduction in recurrent VTE was observed without an increase in major bleeding. • Risk reductions were similar for all subgroups including those with and without thrombophilias. N Engl J Med 2003;348:1425-34

34. Cumulative probability of recurrent venous thromboembolism Duration of Anticoagulation: ELATE • ELATE evaluated 738 patients assigned to indefinite low-intensity therapy versus indefinite conventional intensity therapy. • 16 patients had recurrent VTE in the low-intensity group compared to 6 in the conventional group (1.9 v. 0.7 events per 100 person-years). • There was no significant difference in frequency of major bleeding. N Engl J Med 2003;349:632-9

35. An Approach To Treatment Heparin Risk Stratify Not High Risk High Risk Anticoagulation Consider 1˚ Therapy Warfarin for 6 months If idiopathic PE, continue anticoagulation indefinitely Stop if PE was caused by surgery or trauma Circulation 2003;108:2834-2838

36. Novel Anticoagulants • Fondaparinux is a subcutaneously-administered synthetic pentasaccharide with anti-Xa activity. • It has been approved for thromboprophylaxis in major orthopedic surgery. • It is now FDA-approved for use in PE and DVT. • In REMBRANDT, fondaparinux reduced the rate of recurrent VTE by 64% compared to the LMWH dalteparin. • In MATISSE PE, fondaparinux was equivalent to IV unfractionated heparin. Circulation 2000;102:2726-2731 Bauer K. Pentasaccharides. October 16, 2003.

37. Indicated to reduce the incidence of PE in: PE or recurrent PE despite adequate anticoagulation Patients with contraindications to anticoagulation Open surgical pulmonary embolectomy Limitations: Do not address the thrombotic process Peripheral leg edema can ensue Large venous collaterals can develop and permit PE Filters may be deployed improperly or have technical problems Increased incidence of DVT (at 2 years, 21% v. 12%, p=0.02) No survival benefit Inferior Vena Cava (IVC) Filters Arch Intern Med 2000;160(13):2003-41

38. Retrievable IVC Filters • Recently introduced retrievable IVC filters provide a safe option for patients with transient contraindications to anticoagulation such as trauma, surgery, or temporary bleeding. • Filters must be retrieved within 2 weeks to prevent endothelialization. J Vasc Interv Radiol 2001;12:1053-1058 Radiology 2002;225:835-844

39. Conclusions • Pulmonary embolism is a common and potentially life-threatening disorder. • The work-up of suspected PE requires an integrated application of clinical suspicion, blood tests, and imaging. • Risk stratification is an important component in the evaluation of patients with acute PE. • For a significant subset of patients, VTE represents a chronic illness warranting chronic therapy.

40. The End…