Medical Literature-Based Objectives 1.List the Landmark Radiographic Studies for acute PE evaluation 2.Understand the role of Clinical Decision Rules in

Medical Literature-Based Objectives

1. List the Landmark Radiographic Studies for acute PE evaluation

2. Understand the role of Clinical Decision Rules in acute PE evaluation

3. Consider Special Cases of acute PE

- COPD

- Pregnancy

- IVC Filters

- Submassive PE

Nick Oldnall, Clinical Practice Developer

Pulmonary Angiogram <1990


Perfusion VentilationMismatch

Value of the Ventilation/Perfusion Scanin Acute Pulmonary Embolism

Results of the Prospective Investigation ofPulmonary Embolism Diagnosis (PIOPED)

The PIOPED Investigators

JAMA. 1990;263:2753-2759

Table 1. —PIOPED Central Scan Interpretation Categories and Criteria

High probability >=2 Large (>75% of a segment) segmental perfusion defects without corresponding ventilation or roentgeno-

graphic abnormalities or substantially larger than either matching ventilation or chest roentgenogram abnormalities

>=2 Moderate segmental (>25% and <= 75% of a segment) perfusion defects without matching ventilation or chest roentgenogram abnormalities and 1 large mismatched segmental defect >= 4 Moderate segmental perfusion defects without ventilation or chest roentgenogram abnormalities

Intermediate probability (indeterminate) Not falling into normal, very-low-, low-, or high-probability categories Borderline high or borderline low Difficult to categorize as low or high

Low probability Nonsegmental perfusion defects (e.g., very small effusion causing blunting of the costophrenic angle, cardiomegaly,

enlarged aorta, hila, and mediastinum, and elevated diaphragm) Single moderate mismatched segmental perfusion defect with normal chest roentgenogram Any perfusion defect with a substantially /larger chest roentgenogram abnormality Large or moderate segmental perfusion defects involving no more than 4 segments in 1 lung and no more than

3 segments in 1 lung region with matching ventilation defects either equal to or larger in size and chestroentgenogram either normal or with abnormalities substantially smaller than perfusion defects

>3 Small segmental perfusion defects (<25% of a segment) with a normal chest roentgenogram

Very low probability <=3 Small segmental perfusion defects with a normal chest roentgenogram

Normal No perfusion defects present Perfusion outlines exactly the shape of the lungs as seen on the chest roentgenogram (hilar and aortic impressions

may be seen, chest roentgenogram and/or ventilation study may be abnormal)


Spiral / Multislice CT Angiogram, 2006

The NEW ENGLAND

JOURNAL of MEDICINE

ESTABLISHED IN 1812 JUNE 1, 2006 VOL. 354 NO. 22

Multidetector Computed Tomographyfor Acute Pulmonary Embolism

Paul D. Stein, M.D., Sarah E. Fowler, Ph.D., Lawrence R. Goodman, M.D., Alexander Gottschalk, M.D.,Charles A. Hales, M.D., Russell D. Hull, M.B., B.S., M.Sc., Kenneth V. Leeper, Jr., M.D., John Popovich, Jr., M.D.,Deborah A. Quinn, M.D., Thomas A. Sos, M.D., H. Dirk Sostman, M.D., Victor F. Tapson, M.D.,Thomas W. Wakefield, M.D., John G. Weg, M.D., and Pamela K. Woodard, M.D., for the PIOPED II Investigators

64-year-old woman with pulmonary embolism

Kluge A et al. AJR 2006;186:1686-1696

GADOLINIUM-ENHANCED MAGNETIC RESONANCE ANGIOGRAPHY FORPULMONARY EMBOLISMA MULTICENTER PROSPECTIVE STUDY (PIOPED III)

PAUL D. STEIN, MD; THOMAS L. CHENEVERT, PHD; SARAH E. FOWLER, PHD; LAWRENCE R. GOODMAN, MD; ALEXANDER GOTTSCHALK, MD;CHARLES A. HALES, MD; RUSSELL D. HULL, MBBS, MSC; KATHLEEN A. JABLONSKI, PHD; KENNETH V. LEEPER JR., MD; DAVID P. NAIDICH, MD;DANIEL J. SAK, DO; H. DIRK SOSTMAN, MD; VICTOR F. TAPSON, MD; JOHN G. WEG, MD; AND PAMELA K. WOODARD, MD, FOR THE PIOPED III(PROSPECTIVE INVESTIGATION OF PULMONARY EMBOLISM DIAGNOSIS III) INVESTIGATORS*

ANN INTERN MED 2010: 152:434

Annals of Internal Medicine

Table 1. Reference Test Basis for Diagnosis or Exclusion ofPE in Patients Who Had Magnetic Resonance Angiography

Criteria Patients,n (%)

Diagnosis of PECT angiogram showing PE in a main or lobar pulmonary artery 94 (90)CT angiogram showing PE in a segmental or subsegmental 8 (8)

pulmonary artery in a patient with high clinical 2 (2)probability according to the Wells criteria

High-probability VQ lung scan in a patient with noprevious PE and high or intermediate probabilityaccording to the Wells criteria

Total 104 (100)Exclusion of PE

Normal D-dimer (D-dimer level 500 ng/mL) in a patient with low or intermediate probability according to the Wells criteria 95 (36)

Negative CT angiogram in a patient with low probability 132 (49)according to the Wells criteria

Negative CT angiogram and CT venogram or venous 34 (13)ultrasonogram in a patient with intermediateprobability according to the Wells criteria

Normal VQ lung scan 6 (2)Total 267 (100)

Table 3. Results of MRA and Combined MRA and MRV, by Reference Test

Test Result Reference Test Result, n Total, n

Positive Negativefor PE for PE

MRA resultPositive 59 2 61Negative 17 201 218Technically inadequate 28 64 92

Total 104 267 371

MRA and MRV resultPositive 65 4 69Negative 6 101 107Technically inadequate 33 161 194

Total 104 266 370

MRA magnetic resonance angiography; MRV magnetic resonance venography; PE pulmonary embolism.

Table 5. Recruited Patients and Technical Adequacy, Sensitivity, and Specificity of Combined Magnetic Resonance Angiography and Venography by Clinical Center

Clinical Recruited Technically Inadequate Sensitivity [95% CI], n/N (%) Specificity [95% CI], n/N (%)Center Patients, n [95% CI], n/N (%)

1 68 43/68 (63 [52–75]) 5/6 (83 [36–100]) 17/19 (89 [67–99])2 41 26/41 (63 [49–78]) 6/6 (100 [54–100]) 9/9 (100 [66–100])3 59 21/59 (36 [23–49]) 21/22 (95 [77–100]) 15/16 (94 [70–100])4 77 43/77 (56 [45–67]) 1/1 (100 [3–100]) 32/33 (97 [84–100])5 53 25/53 (47 [34–60]) 14/17 (82 [57–96]) 11/11 (100 [72–100])6 37 10/37 (27 [13–41]) 13/13 (100 [75–100]) 14/14 (100 [77–100])7 35 26/35 (74 [60–89]) 5/6 (83 [36–100]) 3/3 (100 [29–100]) Total 370 194/370 (52 [47–58]) 65/71 (92 [83–97]) 101/105 (96 [91–99])

ContextIs gadolinium-enhanced magnetic resonance pulmonary angiography a feasible and accurate test for diagnosing acute PE?ContributionMagnetic resonance angiography was technically inadequatein 25% of the 371 patients who had the test and identified 57% of the 104 patients with embolism. The sensitivity and specificity of technically adequate tests were 78% and 99%.CautionIn this multicenter study, many patients with suspected pulmonary embolism were ineligible or declined participation.ImplicationBecause magnetic resonance pulmonary angiography is often technically inadequate, consider the test only at centers that routinely perform it well and only for patients with contraindications to standard tests.

—The Editors

Clinical Decision Rules (CDR)

Performance of 4 Clinical Decision Rules in the Diagnostic Management of Acute Pulmonary Embolism A Prospective Cohort Study from the Promethius Study Group

Ann Intern Med. 2011;154(11):709-718.


CDR = clinical decision rule

Ann Intern Med. 2011;154(11):709-718


Ann Intern Med. 2011;154(11):709-718


Ann Intern Med. 2011;154(11):709-718.

Accuracy Indexes of the Clinical Decision Rules in Combination With a Normal d-Dimer Result in Patients With a Suspected Event

Context

•Several clinical decision rules (CDRs) are available to evaluate patients with possible pulmonary embolism (PE). It is not known which CDR, if any, is best to use.

Contribution

•In this multicenter, prospective study, 4 CDRs were used to determine whether PE was likely or unlikely, combined with the results of D-dimer testing, and did equally well at excluding PE or indicating the need for further testing. The CDRs were the Wells rule, the revised Geneva score, the simplified Wells rule, and the simplified revised Geneva score.

Implication

•Provided that these 4 CDRs are used correctly, clinicians can confidently choose them according to personal or institutional preferences to assist in the evaluation of possible PE.

—The Editors

Pulmonary Embolism in Patients with UnexplainedExacerbation of Chronic Obstructive Pulmonary Disease: Prevalence and Risk Factors

Isabelle Tillie-Leblond, MD, PhD; Charles-Hugo Marquette, MD, PhD; Thierry Perez, MD; Arnaud Scherpereel, MD, PhD; Christophe Zanetti, MD; Andre-Bernard Tonnel, MD, PhD; and Martine Remy-Jardin, MD, PhD

Ann Intern Med. 21 March 2006;144(6):390-396

ContextPulmonary embolism (PE) is common in patients with COPD exacerbations;The 2 conditions present similarly.

ContentFor 45 months, every patient presenting with severe COPD exacerbation of unknown cause received an evaluation for PE that included a spiral computed tomography scan and color Doppler ultrasonography of the legs.

CautionsThis was a single-center study.

Pulmonary Embolism in Patients with Unexplained Exacerbation of Chronic Obstructive Pulmonary Disease:

Prevalence and Risk Factors

Ann Intern Med. 2006;144(6):390-396.

Results of Spiral Computed Tomography Angiography in Patients Initially Referred for Suspected Acute Pulmonary Embolism

ContextPulmonary embolism (PE) is common in patients with COPD exacerbations; the 2 conditions present similarly.

ContentFor 45 months, every patient presenting with severe COPD exacerbation of unknown cause received an evaluation for PE that included a spiral computed tomography scan and color Doppler ultrasonography of the legs.

-Twenty-five percent of 197 patients had PE. -Malignant disease, history of VTE, and a decrease in PaCO2 level from

baseline were the only factors associated with PE.

CautionsThis was a single-center study.

ImplicationsWe need additional studies to confirm the high prevalence of PE in unexplained severe exacerbations of COPD and to study the value of routine testing for PE in patients with this clinical presentation.

—The Editors

Estimated radiation absorbed by fetus in procedures for diagnosing PE

The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism for the European Society of CardiologyEuropean Heart Journal 2008

__________________________________________________________Test Estimated radiation

uGy mSv……………………………………………………………………………………………...Chest radiography <10 0.01Perfusion lung scan with technetium 60–120 0.06–012

99m-labelled albuminV/Q scan 200 0.2CT angiography

First trimester 3–20 0.003–0.02Second trimester 8–77 0.008–

0.08Third trimester 51–130 0.051–0.13

Pulmonary angiography by femoral 2210–3740 2.2–3.7access

Pulmonary angiography by brachial <500 <0.5access

Exposure to less than 5 rem (50 mSv) has not been associated with an increase in fetal anomalies orpregnancy loss (American College of Obstetricians 2004).

Advantages and disadvantages of imaging techniques in pregnancy

Ventilation perfusion scan

Advantages

• Low radiation exposure to breast• Low radiation exposure to fetus• High rate of normal scans in pregnancy, 70%

Disadvantages

• Interpretation of test strongly linked to clinical pretest probability. No clinical decision rules validated in pregnancy• Does not offer alternative diagnosis• No accuracy studies in pregnancy available

thelancet.com Vol 375 February 6, 2010


CT pulmonary angiography

Advantages• Could offer an alternative diagnosis• Low radiation exposure to fetus• Better availability than ventilation perfusion scan• More cost effective than other approaches

Disadvantages• Radiation exposure to breast (can be reduced with breast shields)• Technical limitations in pregnancy. Need to modify imaging and injection protocol• No accuracy or outcome studies available• High rate of detection of subsegmental emboli (the clinical significance ofsubsegmental emboli is unclear, so the rate of detection needs to be low)• Theoretical concern about the effect of iodinated contrast on fetal thyroid



MRI

Advantages• No ionising radiation involved• Misses subsegmental emboli

Disadvantages• Insufficient accuracy or outcome data• Most widely used protocols involve gadolinium (which crosses the placenta), forwhich insufficient fetal safety data are available



Compression ultrasonography

Advantages• No exposure to radiation• Non-invasive

Disadvantages• Possible low sensitivity in patients without signs and symptoms of deep vein thrombosis


IVC Filter after Acute PE: Who are we really helping?

The PREPIC Study Group, Circulation 2005

Kaplan-Meier analysis of time to PE over an 8 year period after index thromboembolic event

The PREPIC Study Group, Circulation 2005The PREPIC Study Group, Circulation 2005

The PREPIC Study Group, Circulation 2005

Massive Pulmonary Embolism - ICOPERKucher N, Goldhaber S., et al. Circulation 2006

Overall mortality (A) and cardiovascular mortality (B) in 11 patients with massive PE who received an IVC filter and in 97 patients with massive PE who did not

receive an IVC filter

The IVC Filter: Who Really Has the Better Outcome?

MASSIVE ACUTE PE

Most clinicians would not withhold fibrinolytics from patients with acute PE and hypotension

due to overt RV failure

Should Right Ventricular Dysfunction

Post- Acute PE be Treated Any Differently?

SUBMASSIVE ACUTE PE

Pulmonary hypertension or right ventricular dysfunction without hypotension or shock

Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER)Samuel Z Goldhaber, Luigi Visani, Marisa De RosaLancet 1999; 353: 1386–89

Risk factors and coexisting disorders__________________________________________________________________________________________________________________Variable Yes No Missing Overall __________________________________________________________________________________________________________________Diagnosis of deep-vein thrombosis 1205 1237 12 49·3% Body-mass index ≥29 kg/m2 571 1384 499 29·2% Surgery within 2 months 708 1742 4 28·9% Bed rest ≥5 days 675 1723 56 28·1% Previous deep-vein thrombosis or PE 592 1784 78 24·9% Cancer 551 1894 9 22·5% Current cigarette smoking 403 1878 173 17·7% Chronic obstructive pulmonary disease 303 2138 13 12·4% Trauma 274 2179 1 11·2% Clinical congestive heart failure 256 2179 19 10·5% Current central-venous catheter 183 2266 5 7·5% Left-ventricular ejection fraction <0·4 118 1778 558 6·2% Current chemotherapy 130 2317 7 5·3% Known hypercoagulable state 117 2121 216 5·2% Creatinine >177 μmol/L 125 2313 16 5·1% Platelets <100×109/L 108 2331 15 4·4% Active bleeding requiring transfusion 60 2386 8 2·4% Previous intravenous coagulation filter 21 2427 6 0·9%

Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER)Samuel Z Goldhaber, Luigi Visani, Marisa De Rosa, for ICOPER. Lancet 1999; 353: 1386–89

Cumulative mortality according to status of right-ventricular function on baseline echocardiogram

Final model (815 patients)


Variable Hazard ratio (95% CI)_____________________________________ _______________________Age >70 years 1·6 (1·1–2·3)Cancer 2·3 (1·5–3·5)Clinical congestive heart failure 2·4 (1·5–3·7)COPD 1·8 (1·2–2·7)Systolic blood pressure <90 mm Hg 2·9 (1·7–5·0)Respiratory rate <20/min 2·0 (1·2–3·2)Right-ventricular hypokinesis 2·0 (1·3–2·9)

Kucher, N, Goldhaber S, et al. Arch Intern Med 2005

Survival through 30 days in 1035 patients with PE and systolic arterial BP >= 90 mm Hg at presentation, according to the presence or absence of right RV hypokinesis on the baseline echocardiogram

(adjusted for cancer, congestive heart failure, chronic lung disease, and age)

Kucher, N, Goldhaber S, et al. Arch Intern Med 2005

Grifoni, S. et al. Arch Intern Med 2006

Cumulative incidence of recurrent venous thromboembolism

Follow-up Outcomes in Study Patients Based on In-Hospital Course of Right Ventricular

Dysfunction (RVD)

Outcome (n=155) (n=87) (n=59)

Recurrent VTE

PE-related death

Fatal and nonfatal PE

Death

Grifoni S, et al. Arch Intern Med 2006

No RVD RVD Regression RVD Persistence

15 (10)

2 (1)

6 (4)

21 (15)

* P<.05 vs the other 2 groups by Fisher exact test.

3 (3)

0

2 (2)

11 (13)

14 (24) *

6 (10) *

12 (20) *

13 (24)

Major trials reporting definitions and prognostic significance of RV dysfunction assessed by echocardiography in acute pulmonary embolism___________________________________________________________________________________________________Author n Patient characteristics Echocardiographic criteria Early mortalityRVD(1) vs. RVD( – )……………………………………………………………………………………………………………………………………………………………………………………………..Goldhaber et al. 101 Normotensive RV hypokinesis 4.3 vs. 0%

and dilatation Ribeiro et al. 126 Normotensive and hypotensive RVD 12.8 vs. 0% Kasper et al. 317 Normotensive and hypotensive RV >30 mm or TI >2.8 m/s 13 vs. 0.9% Grifoni et al. 162 BP >=100 mmHg At least one of the following: 4.6 vs. 0%

RV >30 mm or RV/LV>1Paradox septal systolic motionAcT<90 ms or TIPG >30 mmHg

Kucher et al. 1035 BP >=90 mmHg RVD 16.3 vs. 9.4%

All data refer to in-hospital PE-related mortality, except a 30 day all-cause mortality. RVD(+) = patients with RV dysfunction; RVD( – ) = patients with normal RV function.TI = tricuspid insufficiency; AcT = acceleration time of right ventricular ejection; TIPG = tricuspid insufficiency peak gradient.

Guidelines on the diagnosis and management of acute pulmonary embolism. The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism for the European Society of Cardiology. European Heart Journal 2008

Treat Aggressively, Right?

In-Hospital Clinical Events, no. (%)

for Patients with Acute Submassive PE

Heparin Plus Heparin PlusAlteplase Placebo

Event (N=118) (N=138) ‘P’ Value

Death, all causes 4 (3.4) 3 (2.2) 0.71

Escalation of treatment 12(10.2) 34(24.6) 0.004(catecholamines, repeat thrombolysis, intubation, CPR, embolectomy)

Secondary endpoints

Recurrent PE 4(3.4) 4 (2.9) 0.89Major bleeding 1 (0.8) 5 (3.6) 0.29Ischemic stroke 0 1 (0.7) 1.0

Konstantinides, S et al. N Engl J Med 2002

Konstantinides, S et al. New Engl J Med 2002

Treat Aggressively, Right?

Adverse events in relation to thrombolytic treatmentData do not include the 105 patients who did not receive treatment for PE. *Includes four from intracranial haemorrhage and three from stroke.


Received Did not receivethrombolysis thrombolysis(n=304) (n=2045)

_______________________________ ______ _________________

Deaths 70 (23·0%)* 263 (12·9%) Intracranial bleeding 9 (3·0%) 6 (0·3%) Major bleeding 66 (21·7%) 180 (8·8%)>10% decrease in packed-cell volume 39 (12·8%) 114 (5·6%)

during initial hospital stayBlood transfusion during initial hospital stay 35 (11·5%) 157 (7·7%)

S/P Acute PE with RV dysfunction, otherwise stable

Enrollment and Outcome

Stein P.D. et al. Am J Med 2008



Submassive PE: Considerations

Strong consideration for fibrinolysis –

Two Camps: Konstatinides, Goldhaber vs. Stein

Greater than two-fold risk of PE-related mortality – ICOPER

Increased risk of recurrent venothromboembolism – Grifoni

Should receive “strict surveillance” for recurrences

PROPHYLACTIC WARFARIN?

.

Am Heart J. 2012 Jan;163(1):33-38.e1.

Single-bolus tenecteplase plus heparin compared with heparin alone for normotensive patients with acute pulmonary embolism who have evidence of right ventricular dysfunction and myocardial injury: rationale and design of the Pulmonary Embolism Thrombolysis (PEITHO) trial.

-Prospective, multicenter, international, randomized (1:1), double-blind comparison of thrombolysis with tenecteplase vs placebo in normotensive patients with confirmed PE, an abnormal right ventricle on echocardiography or computed tomography, and a positive troponin I or T test result.

-Primary efficacy outcome: composite of death from any cause or hemodynamic collapse within 7 days of randomization.

-Safety outcomes include ischemic/hemorrhagic strokes and other major bleeding episodes.

-180-day clinical and echocardiographic follow-up will be performed.

- Expected enrollment: approximately 1,000 patients.

By determining the benefits vs. risks of thrombolysis in submassive PE, this trial is expected to answer a long-standing query on the management of this patient population.

Documents

Medical Literature-Based Objectives 1.List the Landmark Radiographic Studies for acute PE evaluation 2.Understand the role of Clinical Decision Rules in