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1
Busting Massive and
Submassive Pulmonary
Embolisms
Shermaine Ngo, LMPS Pharmacy Resident
ICU Rotation: Greg Mah
March 22, 2017
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
2
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
3
Meet our Patient!
4
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
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
Background
7
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
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
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
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)
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
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
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
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
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
16
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)
17
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)
18
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
19
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
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.
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
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
23
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
Management
24
25
Cardiology in review. 2016 Jan 1;24(1):19-25.
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)
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
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
Massive PEs
29
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
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)
31
Wan et. al, 2004
32
Circulation. 2004; 110:744-749.
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
33
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
34
35
SUBMASSIVE
Sub-group analysis with Massive PE
36
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
Risk of Bias
37
• 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.
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
38
“…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
39
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
40
Submassive PE
41
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
42
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
PEITHO, 2014
44
American heart journal. 2012 Jan 31;163(1):33-8.
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
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
46
Patients
47
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
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
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
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
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
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
Xu et al., 2015
53
J Thorac Dis 2015;7(5):810-821
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)
55
Risk of Bias
56
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
Results – RVEDD
58
Results – RV/LVEDD Ratio
59
At 6 months
60
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
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
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
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
Catheter-Directed Fibrinolysis
65
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)
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
67
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
ULTIMA, 2014
69
Circulation. 2014; 129:479-486.
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
70
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%
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%
72
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
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JACC Cardiovasc Interv. 2015 Aug 24;8(10):1382-92.
SEATTLE II, 2015
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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
Results
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• 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)
Results
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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%
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
Back to the Patient!
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Management of SH’s PE
• Type of PE:
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Massive PE
What are possible options for treating his PE?
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
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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
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1Uptodate: Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis
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
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.