Acute Pulmonary Embolism: Diagnosis and Management Robert Sidlow, MD November 8, 2010

Why care? PE is the most common preventable cause of death in hospitalized patients ~600,000 deaths/year 80% of pulmonary emboli occur without prior warning signs or symptoms 2/3 of deaths due to pulmonary emboli occur within 30 minutes of embolization Death due to massive PE is often immediate Diagnosis can be difficult Early treatment is highly effective YOU WILL TAKE CARE OF PATIENTS WITH PE!

Pathology At least 90% of pulmonary emboli originate from major leg veins.

Natural History of VTE 40-50% of pts with DVT develop PE, often “silent” PE presents 3-7 days after DVT Fatal within 1 hour after onset of respiratory symptoms in 10% Shock/persistent hypotension in 5-10% (up to 50% of patients with RV dysfunction) Most fatalities occur in untreated pts Perfusion defects completely resolve in 75% of all patients (who survive)

Diagnosis: Clinical Presentation Dyspnea, tachypnea, or pleuritic chest pain most common Pleuritic pain = distal emboli pulmonary infarction and pleural irritation Isolated dyspnea of rapid onset= central PE with hemodynamic sequlea Retrosternal angina like sxs= RV ischemia Syncope=rare presentation, but indicates severely reduced hemodynamic reserve Sxs can develop over weeks In pts with pre-existing CHF or COPD, worsening dyspnea may indicate PE

Non-Specific!!

Diagnosis: Chest X-Ray Usually abnormal, but non-specific Study of 2,322 patients with PE: Cardiac enlargement (27%) Normal (24%) Pleural effusion (23%) Elevated hemidiaphragm (20%) Pulmonary artery enlargement (19%) Atelectasis (18%) Parenchymal pulmonary infiltrates (17%) Chest Radiographs in Acute Pulmonary Embolism: Results From the International Cooperative Pulmonary Embolism Registry. Chest July 2000 118:3338; 10.1378/chest.118.1.33

Diagnosis: ECG Usually non-specific ST/T waves changes and tachycardia RV strain patterns suggest severe PE Inverted T waves V1-V4 QR in V1 Incomplete RBBB S1Q3T3

S1Q3T3 and T wave changes

Diagnosis:Other tests Most patients with PE have a normal pulse oximetry A-a gradient is insensitive and non-specific

Clinical Diagnosis of PE In summary, clinical signs, symptoms and routine tests do not allow for the exclusion or confirmation of acute PE but may increase the index of its suspicion Consider PE in cases of unexplained tachycardia or syncope

Diagnosis-Probability Assessment Implicit clinical judgement is fairly accurate: “Do you think this patient has a PE?” Validated prediction rules standardize clinical judgement Wells Geneva

Proportion with PE 65% 30 10%

Diagnosis D-Dimer SnNOut Fibrin degradation product ELISA tests are highly sensitive (>95%) Non specific (~40%): cancer, sepsis, inflammation increase d-dimer levels SnNOut Negative result excludes PE safely in PE-unlikely patients (using Clinical probability scores)

Spiral CT Direct visualization of emboli. • Both parenchymal and mediastinal structures can be evaluated. • Offers differential diagnosis in 2/3 of cases with a negative scan. BUT… Dye load and large radiation dose Optimally used when incorporated into a validated diagnostic decision tree

3 month VTE rate 0.5% (all non fatal) 1.3% This algorithm allowed for a management decision in 98% of patients presenting with symptoms suggestive of PE

Diagnosis- Summary History and physical examination Then 1,2,3 approach: Clinical decision score D-Dimer test Chest CT 3’. (V/Q scan remains a valid option for patients with contraindication to CT)

Clinical Management After disembarking from a 10 hour airline flight, a 69 year old man w/o past medical hx presents to the ER with acute dyspnea. BP is 120/80 (baseline) and pulse is 120 BPM. Wells score = 5 (intermediate), D-Dimer is positive. Spiral CT shows bilateral pulmonary emboli in >50% of arterial tree.

Congratulations! You’ve made the diagnosis. What’s next?

Question: For the hemodynamically stable patient, how can we differentiate between patients who are going to do well with anticoagulation alone versus those with worse prognosis who might benefit from more aggressive therapy?

RISK STRATIFICATION

Poor Prognostic Signs Hypotension (not caused by arrhythmia, sepsis, or hypovolemia) SBP <90 mm Hg = 53% 90-day all cause mortality SBP drop of 40 mm Hg for at least 15 minutes = 15% in–hospital mortality Syncope= bad Shock= really bad

Poor Prognosis: myocardial injury Troponin levels correlate with in-hospital mortality and clinical course in PE Troponins do not necessarily mean “MI” Significantly increased mortality in patients with troponin level >0.1 ng/ml (O.R.= 6) Normal troponin has very high NPV (99-100%) Prognostic value of troponins in acute pulmonary embolism: a meta analysis. Circulation 2007;116:427-433

Poor Prognosis: myocardial dysfunction Brain natriuretic peptide Elevated levels related to worse outcomes. Low levels can identify patients with a good prognosis (NPV 94-100%) Prognostic role of brain natriuretic peptide in acute pulmonary embolism. Circulation 2003;107:2545-2547

CT evidence of RV dysfunction RV dilation RV/LV short axis >1= pulmonary hypertension RV/LV short axis >1.5= severe PE Leftward septal bowing

Graph of mean values of the RV/LV ratio relative to clinical outcome. Figure 2. Graph of mean values of the RV/LV ratio relative to clinical outcome. Bars represent means and lines represent 95% confidence intervals. The mean RV/LV ratio was significantly higher in patients who died of PE than in the other patients (analysis of variance, P = .018). Brackets show significant differences between groups. van der Meer R W et al. Radiology 2005;235:798-803 ©2005 by Radiological Society of North America

Transverse contrast-enhanced CT scan shows maximum minor axis measurements of the right ventricle (A) and left ventricle (B). Figure 1. Transverse contrast-enhanced CT scan shows maximum minor axis measurements of the right ventricle (A) and left ventricle (B). Note the flattening of the interventricular septum. RV/LV ratio = 1.81. van der Meer R W et al. Radiology 2005;235:798-803 ©2005 by Radiological Society of North America

Echocardiograms before and after Thrombolysis Echocardiography-RV Dilation Echocardiograms before and after Thrombolysis. A 29-year-old woman presented with progressive shortness of breath. A computed tomographic scan of the chest showed a central "saddle" pulmonary embolism. An echocardiogram (Panel A) showed an enlarged right ventricle and hypokinetic motion of the right ventricular free wall. After treatment with alteplase, the right ventricular size and wall motion returned to normal (Panel B). Echocardiograms courtesy of Scott D. Solomon, M.D., and Jose M. Rivero. (Videos of these images are available with the full text of this article at http://www.nejm.org.)‏

RV dysfunction-Echocardiogram Arch Intern Med. 2005;165:1777-1781

RV Dysfunction- Echocardiogram Arch Intern Med. 2005;165:1777-1781

Summary-Elements of PE Risk Stratification

High Risk PE

Approved thrombolytic regimens for pulmonary embolism Streptokinase 250 000 IU as a loading dose over 30 min, followed by 100 000 IU/h over 12–24 h Accelerated regimen: 1.5 million IU over 2 h Urokinase 4400 IU/kg as a loading dose over 10 min, followed by 4400 IU/kg/h over 12–24 h Accelerated regimen: 3 million IU over 2 h rtPA 100 mg over 2 h or 0.6 mg/kg over 15 min (maximum dose 50 mg)

Catheter Embolectomy & Fragmentation An alternative in high-risk PE patients when thrombolysis is absolutely contraindicated or has failed Kucher N Chest 2007;132:657-663

Optimal rx?

Intermediate Risk PE: Hemodynamic stability yet with evidence of RV dysfunction/injury Controversial! Evidence is limited regarding optimal therapy No clinical trial or meta-analysis has been large enough to demonstrate a mortality benefit of thrombolysis compared to anticoagulation alone.

Heparin plus Alteplase Compared with Heparin Alone in Patients with Submassive Pulmonary Embolism Stavros Konstantinides, M.D., Annette Geibel, M.D., Gerhard Heusel, Ph.D., Fritz Heinrich, M.D., Wolfgang Kasper, M.D. and the Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators N Engl J Med Volume 347;15:1143-1150 October 10, 2002

In-Hospital Clinical Events Konstantinides, S. et al. N Engl J Med 2002;347:1143-1150

Conclusions: A combination of alteplase (100 mg given over a two-hour period) and heparin prevented the need for escalation of treatment (with open-label alteplase, catecholamine infusion, or mechanical ventilation) due to clinical deterioration more often than a combination of placebo and heparin. Clinical deterioration usually meant worsening symptoms, especially worsening respiratory failure.

The PEITHO (Pulmonary EmbolIsm THrOmbolysis) Trial Est. completion date November 2012

Bottom line The decision to use thrombolytic therapy in the intermediate risk PE group should be made on a case-by-case basis after carefully weighing the strength of the indication, the potential benefits, the contraindications, and potential adverse effects.

ESC Guidelines: Non-High Risk PE Anticoagulation should be initiated without delay in patients with high or intermediate clinical probability of PE while diagnostic workup is still ongoing Use of LMWH or fondaparinux is the recommended form of initial treatment for most patients with non-high-risk PE 3. In patients at high risk of bleeding and in those with severe renal dysfunction, unfractionated heparin with an aPTT target range of 1.5–2.5 times normal is a recommended form of initial treatment Guidelines on the diagnosis and management of acute pulmonary embolism European Heart Journal (2008) 29, 2276–2315

Non-High Risk PE 4. Initial treatment with unfractionated heparin, LMWH or fondaparinux should be continued for at least 5 days and may be replaced by vitamin K antagonists only after achieving target INR levels for at least 2 consecutive days 5. Routine use of thrombolysis in non–high-risk PE patients is not (yet) recommended, but it may be considered in selected patients with intermediate-risk PE (RV dysfunction, elevated troponin, BNP) and low bleeding risk Guidelines on the diagnosis and management of acute pulmonary embolism European Heart Journal (2008) 29, 2276–2315

Treatment of Acute Pulmonary Embolism First unprovoked PE: rx for at least 3-6 months Recurrent PE or PE and uncured cancer: Consider long term anticoagulation if benefits>risk Agnelli G, Becattini C. N Engl J Med 2010;363:266-274

Case revisited A 69 year old man presents to the ER with acute dyspnea. BP is 120/80 (baseline) and pulse is 120 BPM. Wells score = 5 (intermediate), D-Dimer is positive. Spiral CT shows bilateral pulmonary emboli in >50% of arterial tree. Troponin 0.3 ng/ml Echocardiogram showed RV enlargement with septal bowing into LV. RV function nl. BP remained at baseline 130/80, persistent tachycardia 120 BPM. Risk of 30-day mortality estimated to be ~10%. Given the intermediate risk PE profile and lack of contraindications, after discussion with the patient it was decided that the benefits of t-Pa administration>risks. Pt was admitted to the CCU and 100 mg t-Pa infused over 2 hours; dyspnea resolved over the course of the afternoon. Pt discharged to complete 6 months of warfarin, target INR 2.5. Pt referred to PMD for regular screening colonoscopy. On f/u pt had no evidence of pulmonary htn or post thrombotic syndrome.

IVC Filters May provide lifelong protection against PE Unclear effect on overall survival Complications: DVT (20%) Post thrombotic syndrome (40%) IVC thrombosis (30%) Risk/benefit ratio difficult to determine since no RCT Use when there are absolute contraindications to anticoagulation and a high risk of VTE recurrence Consider in pregnant women with extensive thrombosis Optimal duration of retrievable filters is unclear

Bard Recovery vena cava filter (Bard Peripheral Vascular, Tempe, Arizona) implanted in patient 2 Nicholson, W. et al. Arch Intern Med 2010;0:2010.316-5. Copyright restrictions may apply.

The key is prevention DVT prophylaxis in at-risk patients is quite effective Just do it!

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