Thrombolytics for Acute Pulmonary Embolism:

Clot bustin’ and myth bustin’… maybe?

©iStockphoto.com/dturnerrx

DeAnna W. Turner, PharmD PGY1 Pharmacy Resident

Department of Pharmacy, University Health System, San Antonio, Texas Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center, University of Texas Health Science Center at San Antonio

January 25, 2013

Learning Objectives:

1. Describe the pathophysiology and etiology of pulmonary embolism 2. Identify thrombolytic agents utilized in the treatment of pulmonary embolism 3. Evaluate the role of thrombolytics in acute pulmonary embolism 4. Indicate where the use of thrombolytics for acute pulmonary embolism may be beneficial

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VENOUS THROMBOEMBOLISM I. Definition and Epidemiology1-5

a. Formation of blood clot within a vein b. Venous thromboembolism (VTE) = deep vein thrombosis (DVT) and/or pulmonary embolism (PE) c. Epidemiology

i. Estimated 300,000 to 600,000 people affected yearly in the United States

Increasing incidence with age

a. 1 per 100,000 in childhood; 1 per 100 80 years of age

Incidence slightly higher in men than women

Incidence greater among African Americans and Caucasians d. Approximately two thirds of patients present with DVT and one third with PE

II. Morbidity and mortality1,3

a. Complications associated with VTE include pulmonary hypertension, chronic venous insufficiency, post-thrombotic syndrome, and death

i. Chronic venous insufficiency and post-thrombotic syndrome lifelong conditions characterized by swelling, pain, ulceration, and skin necrosis

b. PE is the primary cause of mortality associated with VTE i. Approximately 10% to 30% of patients die within one month of diagnosis

c. PE is the leading cause of preventable hospital death

III. Pathophysiology2,6-9 a. Virchow’s Triad hypothesis

i. Endothelial injury + changes in blood flow + hypercoagulability = thrombus formation ii. Thrombus composed of red blood cells, fibrin, and platelets

Commonly originate in calf veins

Can occur anywhere in venous system

Figure 1: Virchow’s Triad

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IV. VTE Risk factors1,3,5 a. Lack of identified acquired risk factor in 50% of cases (idiopathic)

Table 1: Risk Factors for VTE

Acquired Transient Acquired Genetic

Advanced age Hormone therapy Family history Malignancy Pregnancy Protein C deficiency

Obesity Immobilization Protein S deficiency Chronic disease Trauma Factor V Leiden Antiphosphlipid

antibodies Surgery Antithrombin

deficiency Hospitalization Sickle cell trait Oral contraceptives Prothrombin G20210A

V. Clinical manifestations3,5,6,10-12

a. DVT i. Up to half of people with DVT asymptomatic

ii. Pain, tenderness, swelling, warmness to touch, and erythema most common signs and symptoms

b. PE i. Arises when a section of clot breaks off and lodges in pulmonary arteries

ii. Symptoms generally appear when 20% to 30% of lung vasculature occluded iii. Cardiac arrest can occur within one to two hours following symptom onset iv. Right ventricular dysfunction (RVD)

Associated with a 66% increase in mortality

Right ventricular (RV) afterload increases as embolic burden increases

RV dilation follows with release of cardiac enzymes

Hypokinesis develops, cardiac output decreases, and cardiac arrest follows v. Sudden death documented as first symptom in approximately 25% of patients

Figure 2: Signs and Symptoms of PE

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Pe

rce

nta

ge

Signs and Symptoms

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VI. PE Diagnosis2,7,12,13 a. Clinical assessment

i. Pretest probability assessment

Wells Score and Revised Geneva Score (APPENDIX A and B)

1st step when VTE suspected; based on medical history and physical examination

Risk divided into low, intermediate, or high probability categories b. Laboratory studies

i. D-dimer

Product of fibrin degradation

Level >500 ng/ml considered abnormal

Fast, noninvasive, and inexpensive

95% sensitivity; negative predictive value a. Elevated D-dimer concentrations can also be seen in the presence of

malignancy, inflammation, or surgery b. Predictive value improved when used in combination with pretest probability

assessment c. Imaging techniques

i. Chest computed tomography (CT) with contrast ii. Ventilation-perfusion (V/Q) lung scan

V/Q mismatch = normal ventilation; perfusion defect iii. Pulmonary angiography

Gold standard; most invasive and expensive

Usually reserved for patients with negative noninvasive tests and high clinical probability

d. Assessment of RVD i. Increased biomarkers

Cardiac troponin T >0.07 ng/ml a. Directly correlates with degree of RVD

Brain natriuretic peptide (BNP) 600 pg/ml ii. Electrocardiogram

New right bundle branch block (RBBB)

T-wave inversion in leads V1-V4

S1Q3T3 pattern iii. Echocardiogram

Pulmonary hypertension

Right ventricular dilatation and hypokinesis VII. PE Management and treatment14-18

a. Anticoagulation i. Halts clot propagation and inhibits recurrent thrombus formation

ii. Agents

Unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and fondaparinux

Eventually bridged to warfarin or rivaroxaban for long-term treatment b. Thrombectomy

i. Catheter-directed or surgical ii. Reserved for unstable patients who have:

Contraindication to thrombolysis

Failed thrombolysis

Shock c. Thrombolytics

i. Considered standard of care in MPE

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ROLE OF THROMBOLYSIS IN PULMONARY EMBOLISM I. American Heart Association classification of PE14,19

a. Low-risk PE: Acute PE and the absence of the clinical markers or adverse prognosis that define massive or submassive PE

b. Submassive PE: Acute PE without systemic hypotension but with either RVD or myocardial necrosis c. Massive PE (MPE): Acute PE with sustained hypotension, pulselessness, or persistent profound

bradycardia i. Sustained hypotension defined as: Systolic blood pressure <90 mmHg for at least 15 minutes

or requiring inotropic support, not due to a cause other than PE ii. Profound bradycardia defined as: Heart rate <40 bpm with signs and symptoms of shock

II. Thrombolytic agents14,20-26

a. Mechanism of action: Act by converting the pro-enzyme plasminogen to plasmin, leading to degradation of the fibrin matrix within thrombus

b. Selective agents i. Bind preferentially to clot-bound plasminogen

ii. Alteplase most commonly used; approved indication for MPE iii. Tenecteplase and reteplase not approved for use in MPE

c. Nonselective agents i. Activate clot-bound and circulating plasminogen

ii. Streptokinase

Derived from group C -hemolytic streptococci

Use limited due to antigenic potential – exacerbates hypotension

Approved indication for MPE; not available in the United States iii. Urokinase

Use limited due to concentration needed for PE lysis

Approved indication for MPE; not available in the United States d. Superiority of one thrombolytic regimen approved for MPE over another not clearly established

Table 2: Summary of Selective Thrombolytic Agents

Alteplase Tenecteplase Reteplase

Dose 100 mg IV infusion

over 2 hours

Weight-adjusted IV bolus over 5-10 sec (APPENDIX C)

10 units IV bolus x 2 30 mins apart

T ½ <5 mins Initial: 20-24 mins

Terminal: 90-130 mins 13-16 mins

Excretion Hepatic Hepatic Hepatic and renal Fibrin specificity ++ +++ +

FDA approved for MPE? Yes No No

Adverse events Bleeding complications biggest limitation to therapy

Intracranial hemorrhage most devastating Contraindications APPENDIX D

FDA = Food and Drug Administration; IV = intravenous; mins = minutes; sec = seconds

III. 2012 updates to the Antithrombotic Therapy and Prevention of Thrombosis American College of Chest

Physicians Guidelines17 a. Thrombolytics recommended in hemodynamically unstable patients with MPE b. Thrombolytics not recommended for hemodynamically stable patients with submassive PE and RVD c. Patients with low-risk PE should not receive thrombolytic therapy

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CLINICAL QUESTIONS I. With weak recommendations and the increased risk of bleeding complications, should thrombolytics be

considered in acute pulmonary embolism, and if so, what dose should be used? II. Factors to consider during evaluation

a. Thrombolytic treatment: Was a bolus dose used? Infusion time? b. Elapsed time between cardiac arrest and initiation of thrombolytic c. Outcomes: Survival to hospital discharge? Recurrent PE? d. Adverse events: Bleeding complications? Neurologic sequelae?

THROMBOLYTICS IN ADVANCED CARDIAC LIFE SUPPORT I. Sudden cardiac arrest27-30

a. Abrupt cessation of spontaneous circulation and ventilation with hemodynamic collapse b. Requires intervention for restoration of spontaneous circulation c. Estimated 300,000 to 500,000 cardiac deaths annually in the United States

i. 43,717 cardiac deaths reported in Texas in 1999

26,004 due to sudden cardiac death d. Approximately 70% of sudden cardiac arrests caused by acute myocardial infarction (AMI) and massive

pulmonary embolism (MPE) e. Major health dilemma with poor prognosis

II. Advanced Cardiac Life Support (ACLS)31

a. Multi-stage algorithms developed b. Divided into two groups based on cardiac arrest rhythms:

i. Shockable = pulseless VT and VF ii. Non-shockable = PEA and asystole

III. Thrombolytics during cardiopulmonary resuscitation (CPR)27,32-34

a. Two proposed mechanisms: i. Local effects at site of pulmonary thrombosis

ii. Prevents “no-reflow” phenomenon

Cardiac arrest and CPR associated with coagulation activation

Inadequate endogenous fibrinolysis

Microthrombi develop throughout circulatory system

Microcirculation impaired, contributing to cardiovascular and cerebral dysfunction

Thrombolytic therapy leads to improved microcirculatory reperfusion and hemodynamic stability

b. Advantages: i. Administered without need for specialty services required of surgery (interventional radiology)

ii. May lyse smaller emboli located in distal pulmonary vasculature not accessible to surgeons c. Disadvantages:

i. PE diagnosis during cardiac arrest may be impossible ii. Indiscriminant use may lead to a higher incidence of bleeding occurrences

IV. Safety of thrombolysis during CPR27,35

a. Ongoing CPR once regarded as a contraindication to thrombolysis i. Chest compressions thought to be potential risk for bleeding complications

ii. No longer considered a contraindication

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Langdon RW, et al. Ann Emerg Med. 1989;18(6):678-80.34 Patient Demographics

33 year old female

Medical History One week prior: abdominal hysterectomy

Presentation Unconscious, apneic, pulseless

Experienced brief syncopal episode and sudden extreme dyspnea earlier the same day

Treatment Prior to Thrombolytic

CPR

Endotracheal intubation and ventilation

Epinephrine*

Atropine*

Sodium bicarbonate*

Dopamine*

IV fluids

rt-PA Course

100 mg total dose o 10 mg bolus via central line o 90 mg continuous infusion over two hours

Administration Delay (after CPR initiation)

30 minutes

Response Palpable pulse and sinus rhythm detected within moments of rt-PA administration

Progressed to tachycardia

SBP 121 mmHg

Remained unresponsive

Transported to cardiac catheterization laboratory o Confirmed MPE on pulmonary angiography

Consciousness regained

Outcome Transported to ICU

BP 118/80 mmHg

Heparin infusion initiated; IVC filter placed

Eight day hospitalization

Experienced pelvic bleeding at site of recent hysterectomy o Required surgical intervention

Discharged home on low-dose warfarin Take Home Points

Successful outcomes rare with CPR alone in MPE

rt-PA administration potentially a life-saving alternative in known or suspected MPE refractory to aggressive CPR

No neurologic complications reported

Embolectomy not practical in arresting patients, nor is it available at all facilities, when contraindications to systemic thrombolysis exist

Non-fatal bleeding complication reported BID = twice daily; ICH = intracranial hemorrhage; TEE = transoesophageal echocardiography; VAP = ventilator associated pneumonia *Doses not reported

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Ruiz-Bailen M, et al. Resuscitation. 2001;51(1):97-101.36 Objective Assess outcomes of thrombolysis during CPR for cardiac arrest due to MPE

Case 1 Case 2 Case 3 Case 4 Case 5 Case 6

Patient Demographics

Female 45 years old

Male 28 years old

Male 34 years old

Male 73 years old

Male 76 years old

Female 56 years old

Medical History Cardiac valve disease

Neoplasm of pancreas

Fracture of patella

None None Protein S deficiency

History of Present Illness

Presented with signs of DVT 5 days post-valve replacement with cardiac arrest 2 days later

Presented with dyspnea, tachypnea, hypotension, cyanosis with cardiac arrest 72 hours after admission

7 days after fracture presented with chest pain, fever, dyspnea, tachypnea with cardiac arrest the next day

Presented with sudden dyspnea, chest pain, tachypnea with cardiac arrest 12 hours later

Presented with syncope followed by dyspnea and cyanosis with respiratory and cardiac arrest 48 hours later

Presented in respiratory arrest after sudden onset dyspnea with cardiac arrest shortly thereafter

Presenting Rhythm

PEA PEA Asystole PEA Asystole PEA

CPR Initiation Immediate After 5 mins After 10 mins

Immediate Immediate Immediate

rt-PA Course* 50 mg bolus + 50 mg bolus after 30 mins

50 mg bolus + 50 mg bolus after 30 mins

50 mg bolus 50 mg bolus + 50 mg bolus after 30 mins

50 mg bolus + 50 mg bolus after 30 mins

50 mg bolus + 50 mg bolus after 30 mins

Administration Delay (after CPR initiation)

60 minutes 30 minutes 30 minutes 15 minutes Immediate 15 minutes

Total CPR Time 70 minutes 45 minutes 90 minutes 30 minutes 5 minutes 40 minutes

Other Treatments

Heparin, dopamine

Heparin None Heparin, dopamine

Heparin, epinephrine

Heparin dopamine

Evidence of RVD Yes Yes Yes Yes Yes Yes

PE Diagnosis (after rt-PA given)

Scintigraphy Necropsy Necropsy Pulmonary arteriography

Scintigraphy Scintigraphy

Neuro Sequelae None Death Death None None None

Post-CPR Complications

Hemorrhage at injection sites

None None None Hemorrhage at injections sites; upper GI bleed

None

Outcome Alive without sequelae after one year

Death Death Alive without sequelae after one year

Developed stroke after one year

Alive without sequelae after six months

Take Home Points

ROSC and survival to hospital discharge successful in 4/6 cases (66.7%)

2/6 patients with mild hemorrhage – no fatal hemorrhages reported o Case 1: no intervention required; Case 5: transfusion of two units required

Potential benefit during prolonged CPR and/or delayed administration

No reported neurologic sequelae from acute event in survivors

Potential life-saving benefits of rt-PA administered on strong clinical suspicion of MPE during cardiac arrest may outweigh risks associated with therapy

rt-PA dosing consistent in case series; however, dose in cardiac arrest not established *First bolus administered over 2-3 minutes; second bolus over 5 minutes

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V. Landmark trials evaluating thrombolytics in ACLS

Abu-Laban RB, et al. NEJM. 2002;246(20):1522-1528.37 Purpose Evaluate effect of rt-PA during CPR in adults with undifferentiated PEA

Design Randomized, double-blind, placebo-controlled study

3 tertiary teaching hospitals and 7 paramedic base stations in Vancouver, Canada

Outcomes Primary:

Survival to hospital discharge Secondary:

ROSC, neurologic outcome, length of stay, hemorrhage

Methods Standard care received by all patients during CPR

Resuscitation efforts continued a minimum of 15 minutes post-infusion

Further treatment at discretion of CPR leader

Administration of aspirin, heparin, or both at discretion of attending physician

Interventions:

Treatment arm o 100 mg rt-PA infused over 15 minutes during CPR

Matching placebo

Results 233 patients enrolled – baseline characteristics similar between groups

36 minutes (median) elapsed from collapse to initiation of rt-PA o Average 32.1 minutes of CPR prior to rt-PA administration

Outcomes

Variable rt-PA (n=117) no. (%)

Placebo (n=116) no. (%)

p-Value

ROSC 25 (21.4) 27 (23.3) 0.85

Died at scene 73 (62.4) 74 (63.8) 0.93

Transported to hospital 39 (33.3) 38 (32.8) 0.96

Enrolled at hospital; died in emergency room

5 (4.3) 4 (3.4) 0.99

Survived to hospital admission 7 (6.0) 6 (5.2) 0.99

Major hemorrhage 2 (1.7) 0 0.50

Minor hemorrhage 1 (0.9) 1 (0.9) 0.99

Length of stay (days) Median Mean

0.4 6.3

0.5 0.5

0.62

Survival to hospital discharge 1 (0.9) 0 0.99

Findings From Autopsy (n=42)

No. of Patients Percent

Cardiovascular Myocardial infarction Hemorrhage

25 9 4

59.5 21.4 9.5

Pulmonary embolism 1 2.4

Miscellaneous 16 38.1

Author’s Conclusions

No evidence of improved survival to hospital discharge with administration of rt-PA during CPR with undifferentiated PEA

96.1% of cardiac arrests occurred out-of-hospital – causes undifferentiated

Earlier administration of rt-PA may yield different outcome (median time = 36 minutes)

Future investigation needed to evaluate earlier administration of thrombolytics

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Take Home Points

rt-PA ineffective for undifferentiated PEA

Poor prognosis associated with out-of-hospital cardiac arrest

Results not generalizable to cardiac arrest patients with known or highly suspected PE in the inpatient setting

Only one confirmed PE – ability to detect treatment effect low

Delay in administration may contribute to adverse effects on outcome

Routine use of thrombolytics in undifferentiated cardiac arrest not recommended AED = automated external defibrillator

Bottiger BW, et al. NEJM. 2008;359(25):2651-2662.30 Purpose Determine whether the use of tenecteplase during CPR can improve survival in adults with

witnessed out-of-hospital arrest

Design Prospective, randomized, open-label, double-blind, placebo-controlled study

66 emergency-medical-service systems in 10 European countries

Outcomes Primary:

30-day survival Secondary:

ROSC, hospital admission, 24-hour survival, survival to hospital discharge

Methods CPR continued for a minimum of 30 minutes after administration of tenecteplase when required

Adjunctive anticoagulation and antiplatelet therapy restricted until hospital admission Interventions:

Treatment arm o Tenecteplase dosing = weight based

Matching placebo

Results 1,050 patients enrolled – baseline characteristics similar between groups

Approximately 18 minutes elapsed from collapse to administration

Outcomes

Variable Tenecteplase (n=525) no. (%)

Placebo (n=525) no. (%)

p-Value

30-day survival 77 (14.7) 89 (17.0) 0.36

ROSC 283 (55) 279 (54.6) 0.96

Hospital admission 281 (53.5) 289 (55) 0.67

24-hour survival 158 (30.6) 171 (33.3) 0.39

Survival to hospital admission 78 (15.1) 90 (17.5) 0.33

Safety endpoints Symptomatic ICH Any ICH Major non-ICH Ischemic stroke

4 (0.8)

14 (2.7%) 40 (7.7) 4 (0.8)

0

2 (0.4) 33 (6.4) 3 (0.6)

0.13

0.006 0.48 1.00

Author’s Conclusions

No survival benefit shown in out-of-hospital cardiac arrest

Pre-hospital emergency care difficult setting for research

Findings do not suggest withholding thrombolytic therapy in patients with a pathologic condition known to be responsive to such treatment

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Take Home Points

Study terminated early due to futility

Out-of-hospital cardiac arrest associated with poor prognosis

Thirty-seven patients with presumed PE enrolled o Only 2 PE confirmed – number too small to determine treatment effect

Tenecteplase used as study drug

Higher frequency of ICH in treatment group

Results not generalizable to patients with suspected MPE in the inpatient setting ICH = intracranial hemorrhage

IV. 2010 updates to the American Heart Association’s ACLS guidelines:31,38

a. Routine use of thrombolytic therapy not recommended in cardiac arrest b. Thrombolytic therapy may be considered in cases of cardiac arrest due to known or suspected MPE

THROMBOLYSIS IN SUBMASSIVE PULMONARY EMBOLISM Konstantinides S, et al. NEJM.

2002;347(15):1143-1150.39

Sharifi M, et al. Am J Cardiol. 2013;111(2);273-277.40

Study Design Prospective, randomized, double-blind, placebo-controlled

49 centers in Germany

Prospective, randomized, controlled, single-center open study

Arizona Purpose Compare effects of heparin + alteplase vs.

heparin + placebo on outcomes of submassive PE in hemodynamically stable patients

Evaluate the role of “safe dose” thrombolysis in reduction of pulmonary arterial pressure in moderate PE in hemodynamically stable patients

Patient Population

TG: Heparin + rt-PA (n=118)

CG: Heparin + placebo (n=138)

TG: Anticoagulation + rt-PA (n=61)

CG: Anticoagulation alone (n=60) Dosing rt-PA = 100 mg total dose

o 10 mg bolus o 90 mg infused over two hours

All patients received UFH

Oral anticoagulation started on day three after randomization

rt-PA = weight based dosing

≥50 kg: 50 mg total dose o 10 mg bolus IVP over one minute o 40 mg infused within two hours

<50 kg: 0.5 mg/kg o 10 mg bolus o Remainder infused within two

hours

All patients received either UFH or enoxaparin ; warfarin started at admission in all patients

Outcomes Primary:

In-hospital death

Clinical deterioration requiring escalation of treatment

Secondary:

Recurrent PE

Major bleeding

Ischemic stroke

Primary:

Development of pulmonary HTN

Composite endpoints of pulmonary HTN and recurrent PE

Secondary:

Total mortality

Bleeding

Recurrent PE

Duration of hospitalization

Composite endpoints of mortality and recurrent PE

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Mortality TG (4/118; 3.4%); CG (3/138; 2.2%) NS

Escalation of treatment significantly higher in CG vs TG (34/138; 24.6% vs. 12/118; 10.2%) p=0.004

Study terminated after interim analysis due to statistically significant difference favoring alteplase treatment

TG (1/61; 1.6%); 3/60; 5%) NS Total mortality plus recurrent PE:

TG (1/61; 1.6%); CG (6/61; 10%) p=0.049

Bleeding Complications

Major bleeding:

TG (1/118;0.8%); CG (5/138;2.9%) NS

Fatal bleeding:

TG (zero); CG (1/138;0.7%) NS Hemorrhagic stroke: zero for both groups

No bleeding complications reported

Recurrent PE TG (4/118; 3.4%); CG (4/138; 2.9%) NS TG (zero); CG (3/60; 5%) p=0.08

Author’s Conclusions

Alteplase in combination with heparin may improve clinical course of submassive PE with low risk of major bleeding complications

Such treatment may prevent further hemodynamic deterioration requiring escalation of treatment

“Safe dose” thrombolysis (≤50% standard alteplase dose) safe and effective for submassive PE

Significant, immediate reduction in pulmonary arterial pressure documented after thrombolysis, which was maintained at 28 month follow-up (p<0.001)

Take Home Points

Thrombolytics not currently recommended for treatment of hemodynamically stable patients with submassive PE; however, these results indicate a potential mortality benefit and a trend towards reduction in PE recurrence

Bleeding complications rare in both studies

Small sample sizes limitation to results

Larger studies needed to evaluate potential benefit in this patient population CG = control group; HTN = hypertension; IVP = intravenous push; NS = non-significant; TG = treatment group;

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RECOMMENDATIONS I. Should thrombolytics be considered in acute MPE? Yes… cautiously.

a. Thrombolytics recommended in hemodynamically unstable patients with MPE in the absence of contraindications

i. Must weigh risk vs. benefit when contraindications exist b. Lack of proven mortality benefit with increased bleeding risks c. Case reports and case series may be associated with reporting bias d. Hemodynamically unstable patient with pulse:

i. rt-PA – 100 mg total dose

10 mg bolus over two to three minutes, followed by 90 mg over two hours e. Pulseless patient:

i. rt-PA – 0.6 mg/kg bolus (50 mg max) ii. Standard ACLS protocols should always be followed in cardiac arrest

iii. Use of thrombolytics should be considered in this patient population when MPE confirmed or highly suspected

Potentially life-saving alternative iv. Do NOT delay therapy for PE confirmation in cardiac arrest when clinical suspicion is high v. Minimize time from collapse to thrombolytic administration when treatment indicated

If MPE confirmed prior to cardiac arrest, administer thrombolytic immediately vi. Can be argued that most contraindications become null in a pulseless patient

vii. Resuscitative efforts should be continued until ROSC achieved or until efforts deemed futile; minimum of 15 minutes

II. Should thrombolytics be considered in acute submassive PE? Maybe in the future.

a. Promising data in this population, with two larger randomized trials in recruitment phase b. Select patients displaying signs of impending clinical deterioration (eg, worsening RVD or hypotension),

may benefit from “early” administration of a low-dose thrombolytic when bleeding risk is low c. Potential benefits beyond trend towards reduction of mortality and/or recurrent PE

i. Reduction of pulmonary HTN complication may provide quality of life benefit d. Results from larger trials needed to confirm findings of smaller studies before comprehensive

recommendation for thrombolytic therapy can be extended to submassive PE

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APPENDICES

APPENDIX A – Wells Score41 APPENDIX B – Revised Geneva Score41 Variable Points

Predisposing factors Previous DVT or PE Recent surgery or immobilization Cancer

+ 1.5 + 1.5 + 1.0

Symptoms Hemoptysis

+ 1.0

Clinical signs Heart rate >100 beats/min Clinical signs of DVT

+ 1.5 + 3.0

Clinical judgment Alternative diagnosis less likely than PE

+ 3.0

Total

Clinical probability (3 levels) Low Intermediate High

0 – 1 2 – 6

7.0

Clinical probability (2 levels) PE unlikely PE likely

0 – 4 >4.0

APPENDIX C – Tenecteplase Dosing26

Weight (kg) Dose <60 30 mg

≥60 to <70 35 mg

≥70 to <80 40 mg

≥80 to <90 45 mg

≥90 50 mg

APPENDIX D – Contraindications to thrombolytics for PE17,23

Absolute

History of cerebrovascular accident Recent intraspinal or intracranial trauma or surgery Active internal bleeding Severe uncontrolled hypertension Known bleeding diathesis Intracranial neoplasm, aneurysm, or arteriovenous malformation

Relative

Age >75 years Pregnancy Uncontrolled hypertension Recent internal bleeding (non-intracranial) Recent trauma, including traumatic CPR Diabetic retinopathy Recent surgery or invasive procedure Pericarditis Ischemic stroke (>3 months prior) Patients currently receiving oral anticoagulation (eg, warfarin)

Variable Points Predisposing factors Age >65 years Previous DVT or PE Surgery or fracture within 1 month Active malignancy

+ 1.0 + 3.0 + 2.0 + 2.0

Symptoms Unilateral lower limb pain Hemoptysis

+ 3.0 + 2.0

Clinical signs Heart rate 74-95 beats/min

95 beats/min Pain on lower limb deep vein at palpation and unilateral edema

+ 3.0 + 5.0 + 4.0

Total

Clinical probability Low Intermediate High

0 – 3

4 – 10

11.0

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