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1 Busting Massive and Submassive Pulmonary Embolisms Shermaine Ngo, LMPS Pharmacy Resident ICU Rotation: Greg Mah March 22, 2017

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Page 1: Busting Massive and Submassive Pulmonary Embolisms · PDF file1 Busting Massive and Submassive Pulmonary Embolisms Shermaine Ngo, LMPS Pharmacy Resident ICU Rotation: Greg Mah March

1

Busting Massive and

Submassive Pulmonary

Embolisms

Shermaine Ngo, LMPS Pharmacy Resident

ICU Rotation: Greg Mah

March 22, 2017

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Outline

• Objectives

• Meet our Patient

• Background on Pulmonary Embolism (PEs)

• Therapeutic Options

• Systemic fibrinolytics in Massive PEs

• Systemic fibrinolytics in Submassive PEs

• Catheter-Directed Fibrinolysis

• Monitoring with Fibrinolytics

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Objectives

1. Describe the different classifications of Pulmonary Embolisms (PE)

2. Describe the general differences in managing non massive, submassive and massive PEs

3. Describe the role of fibrinolytics in managing PEs

4. Describe the monitoring required for fibrinolytics

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Meet our Patient!

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Meet our Patient: SH!

5

ID 53 yo (97kg) Caucasian male admitted on Mar 6, 2017

CC Sudden onset of chest pain and worsening SOB

HPI While doing heavy lifting at work, had sudden onset of sharp chest pain, SOB and multiple syncopal events. For 2 weeks, he also had aching and cramping pain in his left thigh and calf. Ø leg trauma Ø immobilization In ER: 36.4oC, BP 73/25, HR 160, O2sat 96% on 6L O2 CT Angio (Mar 6): Large burden of occlusive and non-occlusive pulmonary emboli involving: • right and left main pulmonary arteries • all segmental and subsegmental branches of all lung lobes. • evidence of right ventricle dysfunction (enlargement of R ventricle) Transferred to ICU: Management of his large burden bilateral PE

Allergies NKDA

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Meet our Patient: SH!

6

Past Medical History Medications PTA

• Asthma (allergies and exercise-induced)

Ø history of VTE or bleeding • Salbutamol 100mcg PRN • Calcium and magnesium supplements

Social Hx: Ø caffeine, Ø smoking, smokes marijuana and drinks ETOH occasionally Financial: Cost concerns (Ø extended healthcare)

Other Diagnostics

• Doppler U/S (Mar 7): DVT in left lower extremity. Ø DVT in right leg • Chest Xray (Mar 6): No focal consolidation, pleural effusions or pneumothorax

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Background

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Pulmonary Embolism

• Obstruction of the pulmonary artery or one of its branches by venous emboli

8

CNS Fever, light-headedness, syncope

RESP Tachypnea, dyspnea at rest and/or with exertion, orthopnea, hemoptysis

CVS Pleuritic chest pain, tachycardia, arrhythmias, audible S4

Clinical Presentation:

Uptodate: Overview of acute pulmonary embolism in adults

Merck Manual (Professional version): Pulmonary Embolism

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Classifications

• Temporal Pattern of Presentation

9

ACUTE SUBACUTE CHRONIC

• Develop symptoms and signs immediately after obstruction of pulmonary vessels

• symptoms and signs present within days or weeks following initial event

• slowly develop symptoms of pulmonary hypertension over many years

Uptodate: Overview of acute pulmonary embolism in adults

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Classifications • Anatomic Location

Other definitions:

• Saddle PE: clot that straddles the bifurcation of the main pulmonary artery (often extending into R and L pulmonary arteries)

• Bilateral PE: clot burden that obstructs both lungs

10

PROXIMAL PERIPHERAL

• Main pulmonary artery/trunk

• Lobar pulmonary arteries

• sub-segmental arteries • segmental arteries

Uptodate: Overview of acute pulmonary embolism in adults

N Am J Med Sci. 2016 Mar; 8(3): 134–142

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11

Classifications

• Physiological Effects

Hemodynamically unstable (1 of the following):

– Sustained hypotension (SBP < 90mmHg or ↓SBP > 40 from baseline) for >15 mins

– Hypotension that requires pharmacological support • Not explained by other causes like sepsis, arrhythmia, hypovolemia, LV dysfunction

– Pulselessness

– Persistent bradycardia (HR < 40bpm with s/s shock)

NON MASSIVE (~70%) SUBMASSIVE (~25%) MASSIVE (~5%)

• Low risk • Intermediate risk • High risk

• Hemodynamically stable • Hemodynamically stable • Hemodynamically unstable

• No right ventricle dysfunction • ~1% mortality rate1

• Right ventricle dysfunction +/- Myocardial necrosis • 5-17% mortality rate2

• +/- Right ventricle dysfunction • ~30% mortality rate3

1Circulation. 2011;123:1788-1830

2Thrombosis Research 125 (2010) e82–e86 3Tex Heart Inst J. 2007; 34(1): 41–46.

Uptodate: Overview of acute pulmonary embolism in adults

Merck Manual (Professional Version): Pulmonary Embolism (PE)

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Right Ventricle (RV) Dysfunction

12

↑ pulmonary vascular resistance (PVR)

Cardiology in review. 2016 Jan 1;24(1):19-25.

↑ RV wall stress

↑ RV pressure load

• RV hypokinesis

• RV dilation

↓ RV cardiac output

↓ LV preload

↓ LV cardiac output

Systemic arterial hypotension

• Pathophysiology

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RV dysfunction

• Assessment: ECG, Chest CT, Echocardiography

– RV dilation or RV systolic dysfunction

– Moderate to severe RV strain (RV hypokinesis or RVSP >40mmHg)

• Biomarkers:

– BNP > 100 pg/mL

– N-terminal pro-BNP > 900 pg/mL

– Troponin I > 0.4 ng/mL

– Troponin T > 0.1 ng/mL

13

Circulation. 2011;123:1788-1830

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RV dysfunction • Right Ventricle End Diastolic Diameter (RVEDD)

– Normal: 24.3 mm ± 6.71

– Dysfunction: RV end-diastolic diameter > 30 mm2

• Right Ventricle/Left Ventricle Diameter Ratio

– RV Dilation: 4-chamber RV diameter divided by LV diameter >0.9 on CT3

– MA by Becattani et al found that a ratio of >0.9 to 1.2 was associated with4:

• 30 day mortality (OR 2.08 (95% CI 1.63–2.66); p<0.00001)

• death due to PE (OR 7.35 (95% CI 3.59–15.09); p<0.00001)

14

1Eur J Echocardiogr (2008) 9 (2): 225-234. 2Arch Med Sci 2012; 8, 6: 957-969

3Circulation. 2011;123:1788-1830 4Eur Respir J 2014; 43: 1678-1690

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Complications and Prognosis

• Prognosis of PE correlates most directly with:

– degree of symptomatic hemodynamic compromise

– asymptomatic RV dysfunction

• Complications:

– Systemic arterial hypotension

– Pulmonary infarction

– Respiratory failure

– Cardiogenic shock

– Cardiac arrest

15

Curr Cardiol Rev. 2008 Feb; 4(1): 49–59.

Uptodate: Treatment, prognosis, and follow-up of acute pulmonary embolism in adults

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Goals of Therapy

• Decrease risk of mortality

• Maintain hemodynamic stability

• Prevent recurrent thromboembolism

• Minimize length of hospital stay

• Reversal or minimization of RV pressure overload and dysfunction

• Minimize adverse drug reactions

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Therapeutic Options • Therapeutic Anticoagulants

– SC LMWH

– IV UFH

– SC Fondaparinux

– Vitamin K antagonist

– Direct Oral Anticoagulants (DOACs)

• Fibrinolytics (Thrombolytics) SYSTEMIC OR CATHETER DIRECTED

– Alteplase (r-tPA)

– Tenecteplase (TNK-tPA)

• Catheter-associated thrombus removal

• Surgical Thrombectomy (massive PE)

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Anticoagulants

• Inhibits the formation of a fibrin clot

– Indirect thrombin inhibitors (UFH, LMWH)

– Factor Xa inhibitors (Fondaparinux)

– Direct thrombin inhibitors (Dabigatran)

– Direct Xa inhibitors (Rivaroxaban, Apixaban)

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Anticoagulants UFH IV bolus, followed by infusion, as per regional nomogram

Dalteparin 200 units/kg SC daily or 100 units/kg SC BID

Enoxaparin 1mg/kg SC Q12H OR 1.5mg/kg SC daily

Tinazaparin 175 units/kg SC once daily

Fondaparinux < 50 kg 5mg SC daily

50-100 kg 7.5mg SC daily

>100kg 10mg SC daily

Rivaroxaban 15mg BID x 21d → 20mg OD

Apixaban 10mg BID x 7d → 5mg BID

Dabigatran 150mg BID after 5-10 days of parenteral AC

Edoxaban 60mg daily after 5-10 days of parenteral AC < 60kg: 30mg daily

Warfarin Overlap with parenteral AC for at least 5 days and until 2 therapeutic INR 2.0-3.0 at least 24 hrs apart

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Fibrinolytics

Fibrinolytic Agent

r-tPA (alteplase)

TNK-tPA (tenecteplase)

MOA Tissue plasminogen activator: binds to fibrin in a thrombus (clot) ⟶ converts entrapped plasminogen to plasmin ⟶ degrades fibrin clot

Dosing Infusion: 100mg IV over 2 hours

Weight-based dosing (0.5mg/kg):

< 60kg 30mg Bolus: 10mg bolus, followed by 90mg over 2 hours

60-69kg 35mg

70-79kg 40mg

Catheter-Directed: 0.5 to 1 mg/hour

80-89kg 45mg

>90kg 50mg

Half-life (mins)

4-10 15-24

No head-to-head trials comparing alteplase to tenecteplase in acute PE

20

Uptodate Monograph: Alteplase Vancouver Acute PDTM: Tenecteplase

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Benefits of Fibrinolysis

• Faster restoration of lung perfusion

– At 24 hrs, 30-35% ↓ in total perfusion defect

– Similar (60-65% ↓) to anticoagulation at 7 ds

• Improve pulmonary artery pressure, arteriovenous oxygenation

• ↓ risk of recurrent PE

• ↓ mortality

21

Pharmacy and Therapeutics 2016 Dec; 41(12): 770–775.

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Contraindications to Fibrinolysis

Absolute:

• Structural intracranial disease

• <2 months intracranial or spinal surgery or trauma

• History of hemorrhagic stroke

• Active bleeding

• Bleeding diathesis

• Nonhemorrhagic stroke within the previous 3 months (excl. ischemic stroke within 4.5h)

Relative:

• Severe uncontrolled HTN (SBP >180, DBP >110)

• Recent (within 2-4 wks) internal bleeding

• Active peptic ulcer

• Current use of anticoagulant with INR > 1.7, PT > 15 seconds

22

Uptodate: Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis

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Complications of Fibrinolysis

• ↑ risk of major bleeding (vs. anticoagulation)

– OR, 2.73 (95% CI 1.91-3.91)1

• ↑ risk of intracranial hemorrhage (vs. anticoagulation) – OR, 4.63 (95% CI 1.78-12.04)1

• ↑ risk of minor hemorrhage2

• Complications may prolong hospitalization2

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1JAMA. 2014 Jun;311(23):2414-21 2Circulation. 2011;123:1788-1830.

Uptodate: Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis

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Management

24

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Cardiology in review. 2016 Jan 1;24(1):19-25.

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Non Massive PE

CHEST Guidelines (2016):

26

Chest. 2016;149(2):315-352. doi:10.1016/j.chest.2015.11.026

Circulation. 2004 Aug 10;110(6):744-9.

(strong recommendation with moderate evidence)

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Submassive PE

CHEST Guidelines 2016:

27

(strong recommendation with moderate evidence)

(weak recommendation with low evidence)

Chest. 2016;149(2):315-352. doi:10.1016/j.chest.2015.11.026

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Massive PE

CHEST Guidelines 2016:

28

(weak recommendation with moderate evidence)

Chest. 2016;149(2):315-352. doi:10.1016/j.chest.2015.11.026

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Massive PEs

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Search Strategy

P Adults with massive (high-risk) PEs (i.e. hemodynamically unstable)

I Systemic fibrinolytics, followed by anticoagulation

C Systemic anticoagulation

O Efficacy: • Mortality • Sustaining of

hemodynamic stability • RV dysfunction • Length of hospital stay • Recurrent VTE (PE)

Safety: • Intracranial hemorrhage • Major hemorrhage • Minor hemorrhage

30

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Search Strategy Results

Database Pubmed, EMBASE

Search Terms

(Alteplase) OR (Tenecteplase) OR (Fibrinolytic) OR (Thrombolytic) AND (Anticoagulant) OR (Heparin) AND (High risk) OR (Massive pulmonary Embolism)

Limits Humans, English, Available online

Results • 1 Meta-analysis • 1 Cochrane Review • 10 RCT • 1 Report • 1 Trial (not randomized)

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Wan et. al, 2004

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Circulation. 2004; 110:744-749.

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Wan et. al, 2004 Design Meta-analysis

Databases • Jan 1980 to Jan 2003 (MEDLINE, EMBASE) • Cochrane Library (2003, Issue 1) • Bibliographies of journal articles and abstracts from major

international meetings

Inclusion 11 RCTs included • Proper randomization • Inclusion of patients with objectively diagnosed symptomatic PE • Comparison of thrombolysis with heparin for initial treatment • Use of objective methods to assess >1 clinical outcomes

(including PE, death and bleeding)

Exclusion 17 RCTs excluded • 1 Non-human • 15 Non-randomized • 1 Mechanical Thrombolysis • 6 had relevant outcome data previously or subsequently reported

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Wan et. al, 2004

Outcomes Primary efficacy outcome: • Composite of recurrent PE or death

Secondary outcomes: • Individual components of primary outcome

Safety outcomes: • Major bleeding • Nonmajor bleeding • Intracranial hemorrhage

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SUBMASSIVE

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Sub-group analysis with Massive PE

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Outcome Thrombolysis Heparin OR (95% CI)

Recurrent PE or death 9.4% 19.0% 0.45 (0.22-0.92)

Recurrent PE 3.9% 7.1% 0.61 (0.23-1.62)

Death 6.2% 12.7% 0.47 (0.20-1.10)

Major bleeding 21.9% 11.9% 1.98 (1.00-3.92)

• Massive PE: included in 5 trials

– Defined as “hemodynamic instability” or determined by angiography

– Jerjes-Sanchez et al’s definition of massive PE: >9 obstructed segments on V/Q lung scan +/- cardiogenic shock

• But also included <9 obstructed segments on V/Q lung scan but with RVD, extensive DVT or both, and s/s of PE

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Risk of Bias

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• Same studies included in the MA by Wan et al, 2004

• Four studies included massive and unknown PE types

– 8% in Ly, 1978 (N = 20)

– 9% in UPETSG, 1970 (N = 160)

– 23% in Tibutt, 1974 (N = 30)

– 71% in Dotter, 1979 (N = 31)

– 100% in Jerjes-Sanchez, 1995 (N = 5)

• Overall, quality of evidence is low

Cochrane Database of Systematic Reviews 2015, Issue 9. Art. No.: CD004437.

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Trials Critique Randomization Unclear to high risk; no information provided for most trials

Allocation Concealment

Unclear; no information provided for most trials

Blinding Unclear; no information provided or high risk for un-blinding

Power Small sample size (OR for composite end-point < 1) Limited power to reliably detect clinically significant differences in outcomes

Attrition bias Unclear to high risk; no information or substantial loss to follow up (45% of heparin group withdrew in Ly, 1978 and 63% loss to follow up in Tibbutt, 1974)

Reporting Bias Unclear risk

Generalizability Trials had a relatively small sample size, and massive PEs only comprised the majority of patient population in 2/5 trials. Definitions of massive PE were not consistent: • Definitions of hemodynamic instability or shock varied among

trials or were not stated • Diagnosis of massive PE were also made by angiography

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“…no evidence for a benefit of thrombolytic therapy compared with heparin for the initial treatment of unselected patients with acute PE”

“…clear benefit is suggested among those at highest risk of recurrence or death, in particular, patients with major pulmonary embolus”

Study’s Conclusion

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Summary

• Overall evidence is weak

– Small trials, unclear to high risk of bias across multiple domains, varying definitions of massive PE, hemodynamic instability and bleeding

– Short-term follow up: 72 hours to 30 days

• Ideally, would like high-quality RCT comparing fibrinolytics to anticoagulants in massive PEs

– Unethical, considering the high risk of mortality associated with massive PEs

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Submassive PE

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Search Strategy

P Adults with submassive (intermediate-risk) PEs (i.e. hemodynamically stable with RV dysfunction)

I Systemic fibrinolytics, followed by anticoagulation

C Systemic anticoagulation

O Efficacy: • Mortality • Hemodynamic stability • RV dysfunction • Length of hospital stay • Recurrent VTE (PE)

Safety: • Intracranial hemorrhage • Major hemorrhage • Minor hemorrhage

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Search Strategy Results

Database Pubmed, EMBASE

Search Terms

(Alteplase) OR (Tenecteplase) OR (Fibrinolytic) OR (Thrombolytic) AND (Anticoagulant) OR (Heparin) AND (Submassive) OR (Intermediate) AND (Pulmonary Embolism)

Limits Humans, English

Results 7 RCTs 1 Prospective study 4 Meta-analysis 1 Systematic Review and Meta-analysis 8 Reviews

43

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PEITHO, 2014

44

American heart journal. 2012 Jan 31;163(1):33-8.

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PEITHO, 2014 Design Multicenter, double-blinded, randomized control trial (Nov 2007 – July 2012)

P Inclusion: • > 18 yo with acute PE

(< 15d) • Normotensive • RV dysfx on ECHO/CT

(RVEDD >30mm, R/LVEDD ratio >0.9, hypokinesis of RV)

• myocardial injury (+ troponin)

Exclusion: • Hemodynamic de-compensation

(need for CPR, SBP<90mmHg>15mins, ↓ > 40mmHg>15mins with signs of end-organ hypoperfusion, hypotension needing tx)

• Known significant bleeding risk (e.g. thrombolytic agents within previous 4ds)

• Any other condition that could place patient at increased risk

I (N = 506) Weight-based tenecteplase IV bolus (30-50mg) and UFH IV infusion (aPTT target 2-2.5 xULN) • UFH bolus not administered if already received an IV bolus or UFH

infusion, or therapeutic doses of LMWH or fondaparinux

C (N = 500) Placebo and UFH IV infusion (aPTT target 2-2.5 xULN) • UFH bolus not administered if already received an IV bolus or UFH

infusion, or therapeutic doses of LMWH or fondaparinux 45

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PEITHO, 2014 O Primary composite outcome:

• Death or hemodynamic decompensation (or collapse) within 7 days Secondary outcomes: • Individual components of primary outcome • Confirmed symptomatic PE recurrence within 7 days • Death within 30 days Safety outcomes: • Major extracranial bleeding within 7 days • Minor and major bleeding within 7 days • Ischemic and hemorrhagic stroke within 7 days • Serious adverse events within 30 days

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Patients

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Characteristics Tenecteplase (N = 506)

Placebo (N = 499)

Age (Mean + SD) 66.5 + 14.7 65.8 + 15.9

Male 47.8% 46.3%

Weight - kg (Mean + SD) 82.5 + 17.9 82.6 + 18.2

Oxygen treatment 86.2% 84.4%

MEDICAL HISTORY

Chronic Heart Failure 4.2% 5.2%

Previous VTE 24.9% 29.5%

Active cancer 8.1% 6.4%

Surgery or major trauma in previous month 6.1% 5.4%

Immobilization 10.9% 11.2%

• Baseline vitals: SBP 130mmHg + 18, HR 93 bpm + 17, RR 21.5 bpm + 6

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Results - Efficacy Outcome Tenec-

teplase (N = 506)

Placebo (N = 499)

Odds Ratio (95% CI)

P-value

NNT

Primary outcome 2.6% 5.6% 0.44 (0.23-0.87) 0.02 34

Death from any cause 1.2% 1.8% 0.65 (0.23-1.85) 0.42

Hemodynamic decompensation 1.6% 5.0% 0.30 (0.14-0.68) 0.002 30

Time b/w random. and 1o outcome 1.54 d + 1.71 1.79 d + 1.60

Recurrent PE b/w random. and day 7 0.2% 1.0% 0.20 (0.02-1.68) 0.12

Fatal 0% 0.6%

Non-Fatal 0.2% 0.4%

Mechanical Ventilation 1.6% 3.0%

Surgical embolectomy 0.2% 0.4%

Rescue fibrinolysis 0.8% 4.6%

Death from any cause b/w random. and day 30

2.4% 3.2% 0.73 (0.34-1.57) 0.42

Still hospitalized at day 30 11.7% 10.0%

Re-hospitalization b/w random. and day 30

4.4% 3.0%

48

c

c

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Results – Safety

49

Outcome Tenecteplase (N = 506)

Placebo (N = 499)

Odds Ratio (95% CI)

P-value

NNH

Bleeding between randomization and day 7

Major extracranial bleeding 6.3% 1.2% 5.55 (2.3-13.39) <0.001 20

Major bleeding 11.5% 2.4%

Minor bleeding 32.6% 8.6%

Stroke between randomization and day 7

Stroke 2.4% 0.2% 12.10 (1.57-93.39)

0.003 46

Ischemic stroke 0.4% 0%

Hemorrhagic stroke (incl. hemorrhagic transformation of ischemic stroke)

2.0% 0.2%

Serious adverse events between randomization and

day 30

10.9% 11.8% 0.91 (0.62-1.34)

0.63

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Randomization Central randomization with use of a computerized Internet-based system (150 centers in 10 countries)

Allocation concealment Unclear

Blinding Patient + investigator; un-blinding only when hemodynamic collapse or any AEs for appropriate management

Baseline characteristics Differences in risk factors for VTE

Power 80% power (N = 474 in each group) for an OR of 0.411, based on est. incidence of 1o outcome of 7% in placebo • Not powered to detect differences in mortality

Statistical analysis Efficacy: ITT analysis (1 excluded from control because of loss of

informed consent)

Safety: mITT analysis (4 excluded from tenecteplase and 1 excluded

from control as no study drug) • Protocol “ITT analysis on superiority of tenecteplase over placebo”

Importance of outcomes Appropriate

Patients accounted for Low exclusion (6/1006)

Reporting bias Reported all outcomes listed in protocol

Funding source Association of university hospitals and Boehringer Ingelheim Ø role in design, conduct, analysis or publication

Generalizability Generalizable to patients with submassive PE (appropriate exclusion criteria) 50

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Study’s Conclusion

“In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke.”

51

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Summary

• Efficacy of tenecteplase:

– Driven by hemodynamic compromise

• Weighing benefits vs. risks:

– Incidence of hemodynamic compromise with: anticoagulation alone ~ 5.0% (NNT = 30 with tenecteplase)

• Rescue fibrinolytics administered in 92% of these patients

• ? Long-term benefits of preventing hemodynamic compromise

– NSS benefit for mortality

• Death d/t hemodynamic decompensation within 7 days: T: 0.19% vs. C: 0.60%

– ↑ risk of stroke (NNH = 46)

– ↑ major extracranial bleeds (NNH = 20)

52

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Xu et al., 2015

53

J Thorac Dis 2015;7(5):810-821

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Xu et al, 2015

54

Design Meta-Analysis

Search PubMed, MEDLINE, EMBASE, Cochrane Library, Chinese Biomedical Literature Databases

Selection RCTs

P Intermediate risk PEs (hemodynamic stability & RVD &/or myocardial injury)

I Thrombolysis + anticoagulation

C Anticoagulation alone, anticoagulation + placebo

Exclusion None stated

Results 7 studies (N = 1631)

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55

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Risk of Bias

56

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Results – Efficacy

• Early-all cause mortality (during hospitalization or within 30 days):

– OR 0.60 (95% CI 0.34 – 1.06), P = 0.08

• Clinical deterioration (sustained hypotension

or shock, requiring treatment escalation, including intubation or mechanical ventilation, cardiopulmonary resuscitation, emergency surgical embolectomy, or emergency catheter fragmentation):

– ✔OR = 0.27 (95% CI, 0.18-0.41), P < 0.00001

• Recurrent PE (within 30 days or during hospitalization):

– ✔OR = 0.34 (95% CI, 0.15-0.77), P = 0.01

57

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Results – RVEDD

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Results – RV/LVEDD Ratio

59

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At 6 months

60

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Results – Safety

Major bleeding within 30ds:

• OR: 2.07 (95% CI, 0.60-7.16)

Minor bleeding within 30ds:

• OR: 5.33 (95% CI, 2.85-9.97)

61

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Study’s Conclusion

Study’s conclusion:

“…thrombolytic therapy for intermediate risk PE patients, without contraindications, may reduce clinical deterioration and recurrent PE, improve RV function and pulmonary hypertension, and is associated with a trend towards a decreased 30-day, all-cause mortality. Although total bleeding risk was higher in the thrombolytic group, differences in the risk of major bleeding risk events were not significant…”

62

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Summary Overall, risk of bias across domains is low

• 2/7 studies were open-label

• No obvious publication bias regarding mortality

Limitations:

• Evaluated different thrombolytics and regimens

• Largest trial (PEITHO) driving the results for clinical deterioration and recurrent pulmonary embolism

• Long-term follow up (~ 6 months) with only 2 studies

63

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Summary of Submassive PE

Considerations

• Main clinical determinants of outcome of PE: age, underlying conditions, clinical signs of right ventricular dysfunction, hypoxemia, burden of PE

• Patient’s Values (regarding benefits and risks of fibrinolytics)

64

GoTs Evidence

Mortality Trend to ↓ mortality but NSS

Hemodynamic stability ✔ ↓ (NNT = 100)Xu et al, 2015

Recurrent PEs ✔ ↓ (NNT = 53)Xu et al, 2015 Statistical significance reached with pooled results, no difference at 6 months

Length of hospital stay ✘(?SS)PEITHO

RV dysfunction ✔ ↓ RVEDD, RV/LV EDD

Adverse Drug Reactions ✘↑ stroke (NNH = 46)PEITHO, 2014

✘↑ hemorrhagic stroke

✘↑ major bleeding ✘↑ minor bleeding (NNH = 5) Xu et al, 2015

Meyer et al. Ann. Intensive Care (2016) 6:19

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Catheter-Directed Fibrinolysis

65

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Catheter-Directed Fibrinolysis • Fibrinolytic agents infused directly into the pulmonary

artery via a pulmonary arterial catheter

CHEST 2016 Guidelines:

Considerations:

• Time to implement (longer than systemic lysis)

• Lower doses can be used and potentially ↓ risk of bleeding

• Local administration of fibrinolytic to clot may ↑ efficacy

• Can perform other mechanical interventions (e.g. embolectomy)

66

Chest. 2016;149(2):315-352. doi:10.1016/j.chest.2015.11.026

(weak recommendation with low evidence)

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Search Strategy

P Acute PEs

I Catheter-directed thrombolytics (CDTs)

C Systemic fibrinoytics

O Efficacy: • Mortality • Sustaining of

hemodynamic stability • RV dysfunction? • Length of hospital stay • Recurrent VTE (PE)

Safety: • Intracranial hemorrhage • Major hemorrhage • Minor hemorrhage

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Search Strategy Results Database Pubmed, EMBASE

Search Terms

(Alteplase) OR (Tenecteplase) OR (Fibrinolytic) OR (Thrombolytic) AND (Anticoagulant) OR (Heparin) AND (Pulmonary Embolism) AND (Catheter-Directed) OR (Catheter)

Limits Humans, English, Available online

Results 0 results comparing systemic fibrinolytics vs. CDT Results for CDTs vs. anticoagulants 1 Systematic Review and Meta-analysis 1 Meta-analysis 2 Prospective Study 5 Retrospective Study 1 RCT 1 Review

68

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ULTIMA, 2014

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Circulation. 2014; 129:479-486.

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ULTIMA, 2014 Design MC, Open-label RCT (Nov 2010 to Jan 2013 in Germany+Switzerland)

P Inclusion: Acute main or lower lobe PE and RV/LV ratio > 1.0 on ECHO

Exclusion: • <18 yo, > 80 yo • PE sx duration >14ds • known significant bleeding risk, • hemodynamic decompensation

I N = 30 IV UFH infusion + Ultrasound-assisted catheter-directed thrombolysis (USAT) of rtPA infusion 1mg/h per catheter x 5 hrs 0.5mg/h per catheter x 10 hrs

C N = 29 IV UFH infusion alone

O Primary outcome: • Difference in RV/LV ratio from baseline to 24 hours Safety outcomes: death, hemodynamic decompensation, major and minor bleeding, recurrent VTE, serious AEs up to 90 ds

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Patients

Baseline vitals: SBP 131, DBP 80, HR 87, RR 20 71

Characteristics USAT (N=30)

Heparin (N = 29)

Age (Mean + SD) 64 + 15 62 + 13

Male 27% 59%

BMI (Mean + SD) 31 + 7 29 + 7

MEDICAL HISTORY

Cancer 17% 7%

Previous DVT 13% 31%

Previous PE 13% 7%

PE SEVERITY

RV/LV ratio (Mean + SD) 1.4 + 0.3 1.3 + 0.2

Bilateral main pulmonary artery embolism 40% 17%

Bilateral lower-lobe artery embolism 73% 86%

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Results

Results USAT (N=30)

Heparin (N = 29)

P-value

PRIMARY OUTCOME

RV/LV ratio – Baseline (mean + SD) 1.28 + 0.19 1.20 + 0.14 P = 0.07

Difference vs. 24 h (mean + SD) 0.30 + 0.19 0.03 + 0.16 P < 0.001

Difference vs. 90 d 0.35 + 0.22 0.24 + 0.19 P = 0.07

CLINICAL OUTCOMES

Hemodynamic decompensation 0% 0%

Deaths 0% 3.4% P = 1.00

Major bleeding 0% 0%

Minor bleeding 10% 3% P = 0.61

Serious Adverse Reactions 0% 0%

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Randomization Unclear

Allocation concealment Open-label

Blinding Open-label

Baseline characteristics Several baseline differences

Power N of 24 per group for power of 80% to detect a mean reduction in RV/LV ratio of 0.10 • Powered for outcome looking at surrogate markers

Statistical analysis Assessed for interobserver agreement for ECHO measurement

Importance of outcomes Main efficacy outcome: surrogate marker

Patients accounted for 2 patients in heparin group were loss to f/u

Reporting bias Protocol not available online

Funding source Funded by EKOS (USAT system); unclear role

Generalizability Appropriate exclusion criteria

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Summary

• Limitations:

– Lacking information on long-term benefits

– Does not provide information on safety or efficacy of CDT when compared to systemic thrombolysis

– Anticoagulation was not monitored, and left to the investigators

• Study’s Conclusion:

– “…confirmed that a fixed-dose USAT regimen was superior to anticoagulation with heparin alone in improving RV dysfunction at 24 hours”

• Summary: improves RV dysfunction faster than anticoagulation, but not powered for other more clinically meaningful outcomes. Study suggests low bleeding risk, when compared to heparin

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SEATTLE II, 2015

75

JACC Cardiovasc Interv. 2015 Aug 24;8(10):1382-92.

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SEATTLE II, 2015

76

Design Prospective, single-arm, MC trial (Jun 2012 to Feb 2013 in US)

P Inclusion: >18yo Massive, sub-massive or proximal PEs, RV/LV diameter ratio >0.9

Exclusion: Stroke, TIA, head trauma, active bleeding…

I N = 150 - Proximal massive (N = 31) or submassive PE (N = 119) Ultrasound-facilitated, catheter-directed, low dose fibrinolysis 24mg of t-PA as 1mg/h for 24 h with a unilateral catheter (unilateral PE) or for 12 h with bilateral catheters (bilateral PE) + Full dose IV UFH (target aPTT of 40-60s during procedure and 60-80s after)

O Primary efficacy outcome: • Change in chest CT-measured RV/LV diameter ratio Primary safety outcome: • Major bleeding within 72 h of procedure initiation

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Results

77

• 25% ↓ in CT-measured RV/LV diameter ratio over 48h

• 30% ↓ in pulmonary arterial systolic pressure by end of procedure and over 48h

• ↓ in mean RV/LV diameter ratio was similar in massive and submassive PE (-0.51 vs. -0.43, P =0.31)

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Results

78

Limitations:

• No comparator

• 16% had IVC filter

• Low target heparin while receiving CDT

Summary:

For acute submassive and massive PEs, US CDT was associated with ↓ in RV dysfunction, in-hospital mortality rate of 2%, 30 day mortality rate of 2.7%, intracranial hemorrhage rate of 0% and major bleeding rate of 10%

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Summary

• Associated with lower bleeding complications

– MA by Bloomer et al: 16 studies (N=860), CDT (+ low dose heparin infusion) was associated with an intracranial hemorrhage risk: 0.35%1

– Systemic thrombolysis associated with rate of ICH up to 3%2

• No head-to-head comparisons with systemic fibrinolytics

• Another alternative to systematic fibrinolytics

– Requires expertise and resources at site

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1Catheterization and Cardiovascular Interventions DOI: 10.1002/ccd.26900 2Uptodate: Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism

and lower extremity deep vein thrombosis

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Back to the Patient!

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Management of SH’s PE

• Type of PE:

81

Massive PE

What are possible options for treating his PE?

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Use of Fibrinolytics

• Indicated for: Massive PEs

– Hemodynamically unstable

– High risk of mortality

• Potential option for: Submassive PEs

– Consider:

• Benefit of ↓ the risk of hemodynamic decompensation

• Overall clinical presentation – E.g. s/s of hypoperfusion (↓ u/o, cold extremities)

• Risk of bleeding

• Patient values

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Choice of Fibrinolytic

• Alteplase

– FDA approved for acute massive PE (use in submassive is off-label)

– Fibrinolytic of choice at VGH for massive PE

• Dosing:

– Massive PE:

• 100mg IV over 2 h

– Submassive PE:

• 10mg IV bolus, then 90mg IV over 2h

83

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When do we start IV UFH?

• Anticoagulant therapy is generally discontinued during thrombolytic infusion1

• In studies looking at massive PEs, IV UFH is generally started following end of fibrinolytic infusion

– Anticoagulation tests (e.g. fibrinogen, PT, TT, aPTT) have been used in studies to dose, but there are no clear guidelines on when or on what parameters IV UFH could be started

• In studies looking at submassive PEs, IV UFH was started at the same time as fibrinolytic infusion

84

1Uptodate: Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis

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Management of SH’s PE

• Type of PE:

• March 6, 2017 to March 9, 2017 AM

– Catheter-directed thrombolysis with alteplase and UFH

• R P/V catheter and L PA catheter: Alteplase 0.5mg/hr

• R PA and L PA catheter: Heparin 250 U/hr

• March 9, 2017: Started on IV UFH

– Bolus of 7000 units followed by 1300 units/hour

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Massive PE

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Monitoring Efficacy Parameters Expected ∆? By Who? Frequency

CNS Temp Afebrile (T <38.3oC) RN Daily

CVS Pleuritic CP, BP, HR, ECHO (RV diameter, pressures)

Absence Vital signs back to baseline If elevated, decrease trend

RN , RPh MD

Daily Baseline, at 6 months and regularly if appropriate

RESP RR, SaO2 SOB, hemoptysis

Vital signs back to baseline Absence

RN, RPh, MD Daily

GU sCr, eGFR, u/o Back to baseline RN, RPh, MD Daily

MSK Swelling, warmth, pain in leg

Absence RN, RPh, MD Daily

HEME aPTT To help dose IV UFH post-fibrinolytics

RN, RPh, MD

At end of infusion

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Monitoring Safety

Parameters Expected ∆? By Who? Frequency

CNS Δ LOC/mental status, severe headache, bizarre behaviour

Presence RN, MD Q6H x 24 hrs Daily

RESP Hemoptysis Presence RN Daily

GI Hematemesis, Melena

Presence RN Daily

GU Hematuria Presence RN Daily

HEME Hgb, Plts ↓ RN, RPh, MD Daily

DERM Abnormal or severe bruising

Presence RN Daily

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Thank you! Questions?

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Appendix

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Pharmacy and Therapeutics 2016 Dec; 41(12): 770–775.