Controversies in the management of

Pulmonary EmbolismJoel Frankel, MD, FACP, FCCP

Plantation General HospitalFebruary 27, 2014

Clinical Case

• 62 y.o. male presents to ED with 48 hours of worsening dyspnea after returning from a 3 day business trip to China

• Vitals: BP 110/60, P 102, O2 sat 86% on RA• PE: Distended neck veins, RR w/o murmur, lungs clear,

normal LE exam• D Dimer = 2496• CT chest multiple thrombi in PA and dilated right

ventricle• Management?

Questions

• Which form of Heparin?– Lovenox (1 mg/kg SC)– Unfractionated Heparin• (80 U/kg bolus; 18 U/kg drip)

• Disposition– ICU– Medicine– Home

Very Simple Goals

• Remember atypical cases• Know why PE is missed• Make your chart bullet proof

Why is the diagnosis delayed or missed?

• Not considering the diagnosis• Presentation too atypical• PE looks like many diseases• The obvious miss• Misinterpretation of studies• Reliance on normal VS

Elevated troponin

• Not just in MI !!!• Myocarditis, tachycardia• CHF, pericarditis, stroke, sepsis• Pulmonary embolism

Who do we miss the diagnosis in?

• Obese females on OCP• Patients with medical comorbidities

The Pulmonary Embolism Rule-Out Criteria (PERC) rule

• Less than 2% chance of PE if clinician pre-test probability < 15% and all of the following:– Age < 50– HR < 100– SpO2 > 96%– No unilateral leg swelling– No hemoptysis– No recent trauma– No h/o VTE/PE– No OCP/exogenous estrogen use

PE myths

• All patients with PE are tachycardic– About 50%

• Hypoxia is usually present• Most patients have risk factors– 20-25 % with risk factors

• Classic presentation common

Protective documentation

• Thought process• Leg exam, Homan’s sign• Risk factor analysis• Clinical gestalt• Clinical decision rule

The chart

• Any patient with cardiopulmonary symptoms• VTE risk factors• Attention to the VS• Leg exam• Evidence that you thought about VTE

Epidemiology

• PE is common– 600,000-900,000 patients annually in US

• PE has high morbidity and mortality– Mortality rate 10 – 17.5% overall– Likely responsible for over 50,000 deaths annually

• Optimal management can improve these outcomes

Questions for Discussion

• Which is the optimal form of heparin to be used in the treatment of PE?

• Do all patients with a new diagnosis of PE need to be admitted?

• When are thrombolytics indicated in the management of PE?

Which is the optimal form of heparin to be used in the treatment of PE?

• Options for bridging anticoagulation in acute PE– Unfractionated heparin (UFH)– Low-molecular weight heparin (LMWH)

• LMWH has multiple potential advantages over UFH

• Use of LMWH for most patients is standard of care and recommended by multiple professional societies

Evidence Supporting Use

• Multiple RCTs have established efficacy and safety between LMWH and UFH for the treatment of PE– 3 month recurrence of VTE: 3.0% vs. 4.4 % (NS)– Major bleeding: 1.3% vs. 2.1 % (NS)

Other Considerations

• LMWH is renally cleared – use with caution with poor renal function

• UFH preferred in hemodynamically unstable patients, especially if considering thrombolysis

• No clear difference in efficacy or safetey when comparing once a day (1.5 mg/kg) vs. twice a day (1 mg/kg) dosing regimens

Do all patients with a new diagnosis of PE need to be admitted?

• Current standard of care is outpatient management for DVT

• 30-40% of patients with DVTs have been found to have asymptomatic PEs

• Although DVT and PE have different outcomes, they exist on the same spectrum of disease (VTE)

• Likely there is some group of low-risk patients with PE that can be managed similarly to DVT

Aujesky et al 2011

• Open-label, multi-center, international, non-inferiority, RCT

• 339 adult patients with confirmed acute PE randomized to inpatient vs. outpatient management

• Outpatients treated with 1 mg/kg LMWH BID until INR > 2.0 for > 2 days

• Primary end-point was recurrent VTE• Secondary end-points included

– Major bleeding– All cause mortality

Inclusion/Exclusion• Patients excluded if any of the

following– O2 sat < 90%– SBP < 100 mmHg– Chest pain requiring IV opiates– Active bleeding– Stroke within 10 days– GI bleed within 14 days– < 75,000 platelets– Cr Clearance < 30– Extreme obesity (>150 kg)– History of HIT– Already being treated with oral

anticoagulant– Any barriers to follow up

Points AssignedAge +1/year

Male +10

Cancer +30

Heart Failure +10

Chronic Lung Disease +10

Pulse > 100 bpm +20

SPB < 100 mm Hg +30

RR > 30 bpm +20

T < 36 degrees C +20

Altered Mental Status +60

Oxygen Sat < 90% +20

Pulmonary Embolus Severity Score of I or II (<86 points)

OutcomesOutpatient Group (n=171)

Inpatient Group (n=168)

P-Value*

90-day outcomesRecurrent VTE 1 (0.6%) 0 (0%) 0.011

Major Bleeding 3 (1.8%) 0 (0%) 0.086

Mortality 1 (0.6%) 1 (0.6%) 0.005

14-day outcomesRecurrent VTE 0 (0%) 0 (0%) 0.003

Major Bleeding 2 (1.2%) 0 (0%) 0.031

Mortality 0 (0%) 0 (0%) 0.003

*P-value represents one-sided p-value for non-inferiority

Erkens et al 2010

• Retrospective cohort study of consecutive patients with confirmed acute PE

• Decision for outpatient treatment by treating physician based on hospital protocol– SPB > 100 mmHG– O2 sat > 92%– No contraindication to LMWH– Does not need admission for other reasons

• Outpatients treated with LMWH• Patient followed-up at 14 days and 90 days

OutcomesOutpatient Group (n=260)

Inpatient Group (n=213)

P-Value*

90-day outcomes

Recurrent VTE 10 (3.8%) 10 (4.7%) 0.654

Major Bleeding 4 (1.5%) 17 (8.0%) 0.001

Readmission Rate 6 (2.3%) 11 (5.2%) 0.135

Mortality* 5 (5%) 57 (26.7%) <0.001

14-day outcomes

Recurrent VTE 1 (0.4%) 4 (1.9%) 0.180

Major Bleeding 0 (0%) 13 (6.1%) <0.001

Readmission Rate 4 (1.5%) 4 (1.9%) 1.0

Mortality* 1 (0.4%) 27 (12.7%) <0.001

Are there other factors that can help risk stratify patients?

• Troponin is a predictor of complicated clinical course or death– NPV for death 96-97%– NPV for complicated clinical course 92-94%

• Pro-BNP is a predictor of mortality or adverse outcomes– NPV for death 99%– NPV for adverse outcome 95%

• RV dysfunction on CT– NPV for PE related death 100%

Take Home Message

• Outpatient management of PE is not common practice currently, but feasible and safe in selected low-risk patients with acute PE

• Standard of care is likely to shift in the near future given pressures to lower resource utilization

• It is reasonable to offer outpatient management in the patient with low PE severity index, normal BP, normal O2 sats, normal EKG, normal troponin, normal pro-BNP, and no evidence of RV dysfunction

• An informed discussion with the patient and careful documentation are necessary to attempt this approach

When are thrombolytics indicated in the management of PE?

• Risk of Bleeding with Thrombolysis in PE– Fatal Hemorrhage: 0.5 %– Intracranial Hemorrhage : 1.8-3.0 %– Major Hemorrhage: 9-13 %

• Potential Benefits of Decreasing– Mortality– PE recurrence– Pulmonary Hypertension– In-Hospital Complications

Differences in Outcomes

• The mortality of patients with PE vary depending on the clinical circumstances– Cardiac Arrest: 66-95%– Massive PE: 22-53%– Submassive PE: 8-13%– Uncomplicated PE: 1-4%

• The clinical circumstances should drive decision making with the use of thrombolytics

Contraindications to Fibrinolytics

• Active internal bleeding• Recent intracranial bleeding• Intracranial tumor or seizure

history• Ischemic stroke within 2

months• Neurosurgery within the

past 1 month• Surgery within the past 10

days• Puncture of non-

compressible vessel within past 10 days

• Trauma within 15 days• Uncontrolled HTN (SBP

> 180; DBP > 100)• Hemorrhagic disorder

or thrombocytopenia (<100,000)

• Impaired hepatic or renal function

• GI bleeding within 10 days

• Pregnancy

Cardiac Arrest

• 10-20% of all PE cases• Dismal outcomes with 66-95% mortality• No RCTs address this clinical scenario• 3 major studies show significant increase in ROSC rate

and trend toward increased survival in cardiac arrest• Overall bleeding complication rare is low when used

in cardiac arrest• Multiple professional societies have supported use of

thrombolytics in this clinical situation

Bottiger et al 2001

• 90 patients with out-of-hospital cardiac arrest undergoing CPR without ROSC within 15 minutes

• 40 patients received 50 mg tPA and 5000 U of heparin as bolus vs. 50 patients with standard ACLS– ROSC: 68% vs. 58% (p=0.026)– Survival to ICU admission: 58% vs. 44% (p=0.009)– 24 hr Survival: 35% vs. 22% (p=0.171)– Hospital Discharge: 15% vs. 8% (NS)

• No CPR related bleeding complications

Lederer et al 2001

• 324 patients with out-of-hospital cardiac arrest undergoing CPR

• 108 received 50 mg tPA as bolus vs. 216 with standard ACLS (retrospective)– ROSC: 70.4% vs. 51.0% (p=0.001)– 24 hr Survival: 48.1% vs. 32.9% (p=0.003)– Hospital Discharge: 25% vs. 15.3% (p=0.048)

• Bleeding complications low– ICH 0.9% vs. 0.9% (NS)– Major Hemorrhage 4.6% vs. 2.3% (NS)

Bozeman et al 2006

• 163 patients in cardiac arrest undergoing CPR not responding to standard ACLS (prospective)

• 50 received 30-50 mg tPA bolus vs. 113 controls with standard ACLS– ROSC: 26% vs. 12.4% (p=0.04)– Survival to ICU admission: 12% vs. 0% (p=0.0007)– 24 hr Survival: 4% vs. 0% (NS)– Hospital Discharge: 4%vs. 0% (NS)

• 1 patient with ICH in tPA group (2%)

Take Home Message

• Although not definitely studied in patients with PE, likely benefit > risk to giving tPA in cardiac arrest with PE is suspected cause

• Consider historical factors or bedside ultrasonography to guide decision making

• When given, administer 50 mg tPA and 5000 U UFH as IV bolus

• May repeat if no ROSC after 15 minutes• If ROSC occurs, start continuous infusion of UFH at

18 U/kg/hr

Massive PE

• 5% of all PE cases• Mortality 22-53%• 5 RCTs that included hemodynamically unstable

patients suggest benefit• Meta-analysis of RCTs showed significant benefit• 2 retrospective studies show trend to benefit• Bleeding complications low in selected patients• Multiple professional societies recommend use of

thrombolytics in this scenario

Wan et al 2004

• Meta analysis of 11 RCTs comparing thrombolysis + heparin vs. heparin alone

• Subgroup analysis of 5 RCTs that included hemodynamically unstable patients

• 128 patients received thrombolysis, 126 received heparin alone

• Efficacy Outcomes– Mortality: 6.2% vs. 12.7% (NS)– Recurrent PE: 3.9% vs. 7.1% (NS)– Recurrent PE or Death: 9.4% vs. 19% (p<0.05)

• Bleeding outcomes: 21.9% vs. 11.9% (p=0.05)

Take Home Message

• Data regarding benefit not definitive, but benefit:risk ratio likely to support use in hemodynamically unstable patients

• Consider use in select patients with CONFIRMED PE and hemodynamic instability keeping in mind patient risk for bleeding complications

• When given, infuse 10 mg tPA as bolus followed by 90 mg infusion over 2 hours

• Should be followed by 80 U/kg bolus of heparin followed by 18 U/kg/hr infusion

Submassive PE

• 23-40% of all PE cases• Increased mortality when compared to

hemodynamically stable patients without RV dysfunction (9.3% vs. 0.4%)

• Multiple studies have definitely shown improvement in hemodynamic or radiographic parameters, though improvement in clinical outcomes remains mixed

Take Home Message

• Treatment of patients with submassive PE with thrombolytics is highly controversial

• Current evidence is conflicting and filled with multiple flaws

• Use of thrombolytics in this situation does not carry overall support from professional societies and is not standard of care

• Use of thrombolytics may be considered in select patients with support from sub-specialists

Future Directions• The Pulmonary EmbolIsm THrOmbolysis (PEITHO) trial is a multi-center

international RCT (double-blinded, placebo controlled) currently underway

• Includes patients with– Confirmed acute PE– RV dysfunction on Echo or CT chest– Elevated Troponin

• Treatment Protocol– Thrombolysis Group: tPA + UFH– Control Group: UFH only

• Outcomes– Primary: Composite of Death or Hemodynamic Collapse < 7 days– Secondary: Death, Hemodynamic Collapse, Recurrent PE, ICH, Major Bleeding

Follow-up on Initial Questions

• Which is the optimal form of heparin to be used in the treatment of PE?– LMWH in most cases

• Do all patients with a new diagnosis of PE need to be admitted?– There may be a group of very low risk patients that can be managed

primarily as outpatients• When are thrombolytics indicated in the management of PE?

– Clearly indicated in cardiac arrest from PE and massive PE without contraindication to fibrinolytics

– Utility in submassive PE unclear– Not indicated in uncomplicated PE