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FSHP 2017 ANNUAL MEETING

Breaking it Down: An Evidence Based Update on ThrombolyticsBreaking it Down: An Evidence Based Update on ThrombolyticsJason Ferreira, Pharm.D., BCPS, BCCCPMedical ICU pharmacistUF Health Jacksonville

2017 ANNUAL MEETING

#FSHP2017DisclosureDisclosure

I do not have any significant financial interest or other relationship with the companies who make/provide these

products/services

2017 ANNUAL MEETING

#FSHP2017ObjectivesObjectives• Describe the pharmacology and pharmacokinetics of

commonly used thrombolytics• Analyze the currently accepted uses and outcomes

associated with thrombolytic therapy in pulmonary embolism (PE)

• Evaluate the most recent literature on the utilization of thrombolytics in PE

2017 ANNUAL MEETING

#FSHP2017Pulmonary EmbolismPulmonary Embolism• Spectrum of disease including

• 79% have evidence of deep vein thrombosis (DVT)

• 50% of proximal DVT will have a PE • Obstruction is the most

important cause of compromised physiology• Release of vasoactive and

bronchoactive agents

Tapson VF. N Engl J Med 2008;358:1037-52 s

2017 ANNUAL MEETING

#FSHP2017Pulmonary Embolism Pulmonary Embolism

Goldhaber S, The Lancet; Apr 24,1999; 353,9162;Tapson VF. N Engl J Med 2008;358:1037-52Fengler BT. Am J Emerg Med 2009;27:84-95Jaff MR. Circulation. 2011;123:1788-1830.

Massive (High)• Hypotension or cardiac arrest • 22 - 58% mortality

Submassive (Intermediate)• Significant variation• Hemodynamically stable • Right ventricle (RV) failure +/- myocardial necrosis• 8 - 13% mortality

Minor (Low)

• <1% mortality • Commonly anecdotal finding

2017 ANNUAL MEETING

#FSHP2017Pulmonary EmbolismPulmonary Embolism• Incidence has increased

• Diagnosis? • 17% of all syncope patients

• 300,000 deaths/year in the U.S. • 26% of unrecognized PE are

eventually fatal • 16% of all hospital deaths

• PE patients 4x more likely to die from reoccurrence

Agnelli G. N Engl J Med 2010;363:266-74Tapson VF. N Engl J Med 2008;358:1037-52Prandoni P. N Engl J Med 2016;375-1524-31

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https://medmcqs.files.wordpress.com/2013/08/pulmonary-embolism.jpg2017 ANNUAL MEETING

#FSHP2017Pathophysiology of Submassive PEPathophysiology of Submassive PE

2017 ANNUAL MEETING

#FSHP2017Submassive Pulmonary EmbolismSubmassive Pulmonary Embolism• Overall 3 month mortality >15%

in submassive PE • Right ventricular dysfunction(RVD)

occurring in 44%• RVD doubles the hazard ratio of

death at 90 days• Significant impact on morbidity

• 3% chronic thromboembolic pulmonary hypertension (CTEPH)

• 36% persistent clinical symptoms

Tapson VF. N Engl J Med 2008;358:1037-52Fengler BT. Am J Emerg Med 2009;27:84-95Jaff MR. Circulation. 2011;123:1788-1830Konstantinides SV, J Am Coll Cardiol 2017;69:1536-44

2017 ANNUAL MEETING

#FSHP2017ThrombolyticsThrombolytics

PAI-1 = plasminogen activator inhibitor 1

http://www.setma.com/article.cfm?ID=3302017 ANNUAL MEETING

#FSHP2017ThrombolyticsThrombolytics• Long half-life

• Prevent re-thrombosis • Allow for bolus administration

• Highly fibrin specific and neutral to plasmin • Reduce the risk of hemorrhagic complications

• Resistant to plasminogen activator inhibitor 1 (PAI-1)• No neurotoxic or neurodegenerative adverse effects • Achieve 100% recanalization

Tsikouris JP. Pharmacotherapy 2001; 21(2):207-217Campbell J. Semin Thromb Hemost 2010;36:529-536Kunadian V. Drugs of Today 2011;47(7):559-570

Fibrin Specificity

2017 ANNUAL MEETING

#FSHP2017ThrombolyticsThrombolytics

Tsikouris JP. Pharmacotherapy 2001; 21(2):207-217

↓ specificity • ↑ circulating plasmin

↓ neutralizers

Systemic fibrinolytic state

Thrombolytic activity - Likely due to plasma clearance

- Potency comparisons are not available

Resistance to inhibitors - Specifically PAI-1

2017 ANNUAL MEETING

#FSHP2017ThrombolyticsThrombolytics

Firs

t gen

erat

ion

•Low fibrin specificity

•Similar efficacy, ↑ adverse effects• ↑ ICH?

•High antigenicity•Direct/indirect

activation

Seco

nd g

ener

atio

n •Recombinant t-PA•Fibrin specific •Moderate PAI-1

resistance•Benchmark for

new thrombolytics•NMDA and

kainate-mediated neurotoxicity

Third

gen

erat

ion •Muntant t-PA

•Highly fibrin specific

•Greater fibrinolytic potency

•Longer half life•High PA-I

resistance

Tsikouris JP. Pharmacotherapy 2001; 21(2):207-217Campbell J. Semin Thromb Hemost 2010;36:529-536Kunadian V. Drugs of Today 2011;47(7):559-570

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2017 ANNUAL MEETING

#FSHP2017Thrombolytics in PEThrombolytics in PE• Evidence establishing benefit stem from massive PE

• Jerjes-Sancez et al. sought to randomize 40 patients • Stopped after 8 patients • 4 streptokinase patients survived vs. 4 heparin patients expired • Future studies exclude massive PE

• Evidence in submassive PE continues to waiver• Inconsistent• Reliant on secondary outcomes

Wan S. Circulation 2004;110:744-9Jerjes-Sanchez C. J Thromb Thrombolysis 1995;2:227-9Fengler BT. American Journal of Emergency Medicine 2009;27:84-95

Meta-analysis of the only 5 RCTs

↓ the risk of death or recurrent PE by 55%

Number needed to treat (NNT) = 10

2017 ANNUAL MEETING

#FSHP2017Thrombolysis in Submassive PEThrombolysis in Submassive PE

Tapson VF. N Engl J Med 2008;358:1037-52Fengler BT. Am J Emerg Med 2009;27:84-95Jaff MR. Circulation. 2011;123:1788-1830Konstantinides SV, J Am Coll Cardiol 2017;69:1536-44

Mortality < 3% with anticoagulation Possible benefits in secondary outcomes- CTEPH - Recurrent PE - Functional status NNT ~60

Effect size on mortality <1% Significant bleeding riskLimited data on long term outcomes Number needed to harm - 18 major bleeding - 78 intracranial

2017 ANNUAL MEETING

#FSHP2017Thrombolysis in Submassive PEThrombolysis in Submassive PE• MAPPET-3 prospective RCT (n = 256)

• Age >70, female & hypoxemia ↑ risk of poor outcomes • Escalation of therapy as an endpoint may skew results

Konstantinides S. N Engl J Med 2002; 347(15):1143-1150

TOPCOAT (n = 83)

2017 ANNUAL MEETING

#FSHP2017Thrombolysis in Submassive PEThrombolysis in Submassive PE

KlineJA. J Thromb Haemost 2014; 12: 459–68.Becattini C. Thrombosis Research 2010;125:e82-e86

Acute submassive PE with RVD

Dalteparin + tenecteplase(TNK)

Adverse outcomes at 5 days

Functional capacity at 30 days

TIPES (n = 58)Acute submassive PE with RVD

Heparin + TNK

RVD at 24 hours

RVD at 7 days or discharge

TOPCOAT (n = 83)Severe adverse effects

7% placebo vs. 2.5% TNK

Poor 90 day functional capacity 11.6% placebo vs. 2.5% TNK

Recurrent VTE 2.3% placebo vs. 2.5% TNK

Heart failure functional class > 320.5% placebo vs. 5.4% TNK

(p=0.051)

TIPES (n = 58)

Major and minor bleeding 6.6% placebo vs. 53.5% TNK

Primary outcome Major bleeding

2017 ANNUAL MEETING

#FSHP2017Thrombolysis in Submassive PEThrombolysis in Submassive PE• PEITHO trial (n = 1005)

Meyer G. N Engl J Med 2014;370;1402-11

Popu

latio

n Acute PERVD + myocardial necrosis

Inte

rven

tion Heparin + TNK

Out

com

es Mortality or decompensation

Major/minor bleeding

TNK Placebo p-valuePrimary outcome 13 (2.6) 28 (5.6) 0.02

Death from any causeHemodynamic decompensation

6 (1.2)8 (1.6)

9 (1.8)25 (5)

0.420.002

2017 ANNUAL MEETING

#FSHP2017Thrombolysis in Submassive PEThrombolysis in Submassive PE

Sista AK. Vascular medicine 2016;21(1):47-52

Right ventricle

dysfunction Death

CTEPHBleeding complications

Recurrent pulmonary embolism

Quality of life

Persistent symptoms

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2017 ANNUAL MEETING

#FSHP2017Thrombolysis in Submassive PEThrombolysis in Submassive PE

Sista AK. Vascular medicine 2016;21(1):47-52

Randomized

Non -Randomized

< 6 month follow up

Konstantinides SV et al. (2017)Keiko et al. (2010)Pengo et al. (2004)Kline et al. (2009)Stevinson et al. (2007)Chow et al. (2014)Ribeiro et al. (1999)Sharma et al. (2000)> 6 month follow up

PEITHO (2014)MAPPET-3 (2002)TOPCOAT (2014)TIPES (2010)ULTIMA (2014)Goldhaber et al. (1993)

ICOPER (1999)MAPPET (1997)Grifoni et al (2000)SEATTLE II (2015)PERFECT (2015)

Fasullo et al. (2011)MOPPETT (2013)

2017 ANNUAL MEETING

#FSHP2017Long Term Outcomes in PELong Term Outcomes in PE

Kline JA. Chest 2009;136:1202-1210Sharma G. Vascular Medicine 2000;5:91-95

• 210 patients with submassive PE → 21 received rt-PA • ECHO at baseline and 6 months• 46% of heparin patients had residual symptoms •Dyspnea at rest or exercise intolerance• 28% of rt-PA had signs of PH

Kline et al.

• Longest follow up study 7.3-7.5 years after SK or UK• Patients receiving heparin

• Higher mean pulmonary artery pressure(PAP), and pulmonary vascular resistance (PVR)

• Larger increase in mean PAP with exercise • 72.7% heparin v. 33.3% thrombolytic NYHA II or III

Sharma et al

2017 ANNUAL MEETING

#FSHP2017Long Term Outcomes in PELong Term Outcomes in PE

Sharifi M. Am J Cardiol. 2013;111:273–7.

MOPETT trial Primary objective: Pulmonary

hypertension 28 month follow up

CTEPH 16% vs. 57%p < 0.001

Total mortality 1.6% vs. 5%p = 0.3

114 patients

Mortality + recurrent PE 1.6% vs. 10%

p = 0.049

Mortality 2-5 X higher then all similar trials?

Use of modified Bernoulli equation for diagnosis of pulmonary hypertension - Misdiagnoses in 48-54% of patients

- First trial to use RA/LA dimension to determine RA pressure- 4v2 + right atrial pressure

2017 ANNUAL MEETING

#FSHP2017Long Term Outcomes in PELong Term Outcomes in PE• Largest long term follow up study

• Observational analysis of PEITHO patients

• Overall mortality 19.2% • Non-PE related beyond 30 days• 20.3% TNK vs. 18% placebo

Konstantinides SV, J Am Coll Cardiol 2017;69:1536-44

PEITHO (n = 1006)

Patients consent to long term follow up(n = 709)

Median duration of 37.8 months

Clinical/ECHO follow up

TNK (n = 175)

Placebo (n = 183)

Persistent symptoms (%) 36 30NYHA class III or IV (%) 12 10.9

TNK (n = 144)

Placebo (n = 146)

Low probability of PAH (%) 60 68Diagnosis of CTEPH (%) 12 10.9sPAP, median (IQR) 30.0 (24.0–35.0) 30.0 (25.0–35.0)RVD (%) 4.2 3.4

2017 ANNUAL MEETING

#FSHP2017Thrombolytic Induced Bleeding Thrombolytic Induced Bleeding • Dependent on the disease state • ICH rates in stroke

• 4-7% with IV thrombolytic• 8-12% with intra-arterial (IA) thrombolytic

• ICH rates in PE range from 0.5-1.3% in controlled trials • 3% in ICOPER trial looking at “real-world” data

• Major bleed risk in PE of 12.9% v. 8.6% with anticoagulation alone

4-fold age >70

12.1% risk with invasive procedure

Weight < 65 kg

Major bleeding

Age > 70

Weight < 70 kg

Hypertension on admission

ICH

Goldhaber S, The Lancet; 1999; 353,9162;Mikkola KM, Am Heart J 1997;134:69-72Agnelli G, N Engl J Med 2010;363:266-74Simoons ML, Lancet 1993; 342:1523-8.Wang C. Chest 2010; 137(2):254-262

2017 ANNUAL MEETING

#FSHP2017Risk stratification Risk stratification • Multiple proposed scoring systems to stratify care

• Identify high risk → greatest potential risk • Identify low risk → outpatient management

• PE severity index (PESI) • Best predictive ability → PESI IV and V

• Simplified version pending validation• Use of biomarkers improves predictability

• cTnI + PESI → ↑ prediction of hemodynamic instability

• Correlation with thrombolytic therapy?

PE severity index (simplified))

Prognostic factors of PE (PREP)

Shock Index

Utrecht prediction score (UPS)

Multicenter study of PE (EMEP)

Global registry of Acute Coronary events (GRACE)

Genevia/Revised prognostic score

Ellias A, BMJ open 2016;6:e010324. doi:10.1136/bmjopen-2015-010324

Risk strataClass I 65 or lessClass II 66 – 85Class III 85 – 105Class IV 106 – 125Class V > 125

Parameter PointsAge YearsMale sex +10Cancer +30 Chronic heart failure +10Chronic pulmonary disease +10Pulse ≥ 110 bpm +20SBP < 100 mmHg +30 Respiratory rate ≥ 30 bpm +20Temperature < 36 C +20Altered mental status +60Arterial O2 saturation < 90% +20

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2017 ANNUAL MEETING

#FSHP2017Risk stratification Risk stratification

Thrombolysis in submassive PE has

not been successfully

implemented

Disproportionate risk without

consistent benefitMinimize risk and shift endpoints?

Secondary outcomes

- Long term impact - Length of stay - Cost of care

2017 ANNUAL MEETING

#FSHP2017Half-doseHalf-dose

Goldhaber SZ. Chest 1994; 106; 725-726 Wang C. Chest 2010; 137(2):254-262

Goldhaber et al. Wang et al. Patients 140 submassive PE 118 massive and submassive PE

Treatment t-PA 0.6 mg/kg over 15 mins (max 50 mg) + heparin (60-85 sec)

50 mg over 2 hrs + nadroparin

Efficacy Mortality twice as much in low dose No difference? Efficacy in anatomically massive PESimilar improvements in hemodynamics

Bleeding Bleeding twice as much with standard doseDeaths from bleeding twice as high in low dose

Total and major bleeding more in standard dose

Notes Underpowered to show a difference Significantly more bleeding in patients <65 kg or a BMI <24 kg/m2

“Safe-dose”“Safe-dose”Anticoagulation

initiated

Enoxaparin 1mg/kg Max 80 mg

Thrombolysis initiated 10 mg

bolus + remainder of tPA 0.5 mg/kg (max

50 mg) over 2 hrs

Heparin 70 U/kg (max 6000) bolus +

10 U/kg/hr (max 1000)

1.5-2 x aPTT

Thrombolysis initiated 10 mg

bolus + remainder of tPA 0.5 mg/kg (max

50 mg) over 2 hrs

3 hours after thrombolysis

1mg/kg enoxaparin Q12h

Heparin 80 U/kg bolus + 18

U/kg/hr1.5-2 x aPTT

Sharifi M. Am J Cardiol. 2013;111:273–7. 2017 ANNUAL MEETING

#FSHP2017

• MOPETT trial (n = 121)• Theoretically safer regimen vs. placebo • Reduced tPA and heparin dosing

• Clinical outcomes • ↓ rate of death or recurrent PE• Shorter hospital stay

• 2.2 vs. 4.9 days; p < 0.001

• Safety outcomes• No bleeding with thrombolysis

2017 ANNUAL MEETING

#FSHP2017“Safe-dose”“Safe-dose”

Sharifi M. Clin Cardiol 2014;37(2):78-82

Drip

50 mg tPA + low dose heparin- 49% RV enlargement - 61% cTnIelevation

Dru

g Rivaroxaban 20 mg daily - No bleeding events - No deaths - Significant reduction in PASP at 6 months

Disc

harg

e Discharge after oral therapy initiation- Average LOS 1.9 days - Included 12 severe PE, 6 massive PE

n = 98

2017 ANNUAL MEETING

#FSHP2017Interventional Therapy Interventional Therapy • Better or equivalent outcomes

• Higher drug concentration • Less bleeding • Less drug required

• Ultra-sound assistance catheter (USAT)?• Fibrin disruption• Evidence suggests non-significant

• Requires skilled operator

Sista AK, Vascular medicine 2016;21(1):47-522017 ANNUAL MEETING

#FSHP2017Interventional Therapy Interventional Therapy • ULTIMA study (n = 59)

• USAT vs. heparin • 1mg t-PA/catheter for 5 hours 0.5 mg/catheter

for 10 hours• Heparin titrated to anti-Xa 0.3-0.7 IU/mL

• Outcomes• Faster resolution of RV pressures

Kucher N, Circulation 2014;129:479-486

RV/LV ratio > 1

Centrally located PE

Catheter placed

depending on vessel

involvement 1 vs. 2

USAT Heparin p-valueRV/LV ratio reduction 0.30 + 0.2 0.03 + 0.16 <0.001RVD at 90 days, n 2.2 + 0.9 1.5 + 0.9 0.01Major bleeding (%) 0 0Minor bleeding (%) 3 (10) 1 (3) 0.61Hospital LOS (days) 8.9 + 3.4 8.6 + 3.9 0.8

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2017 ANNUAL MEETING

#FSHP2017Interventional Therapy Interventional Therapy • ULTIMA study (n = 59)

• USAT vs. heparin • 1mg t-PA/catheter for 5 hours 0.5 mg/catheter

for 10 hours• Heparin titrated to anti-Xa 0.3-0.7 IU/mL

• Outcomes• Faster resolution of RV pressures

RV/LV ratio > 1

Centrally located PE

Catheter placed

depending on vessel

involvement 1 vs. 2

USAT Heparin p-valueRV/LV ratio reduction 0.30 + 0.2 0.03 + 0.16 <0.001RVD at 90 days, n 2.2 + 0.9 1.5 + 0.9 0.01Major bleeding (%) 0 0Minor bleeding (%) 3 (10) 1 (3) 0.61Hospital LOS (days) 8.9 + 3.4 8.6 + 3.9 0.8

Kucher N, Circulation 2014;129:479-486

PERFECT (n = 101)

2017 ANNUAL MEETING

#FSHP2017Interventional Therapy Interventional Therapy

Piazza G, J Am Coll Cardiol Intv 2015;8:1382-92Kuo WT, Chest 2015;148(3):667-673

Massive (n=28) & submassive (n=73) proximal PE with RV/LV ratio > 0.9

Multi-center registry28 mg tPA (n =76) and 2,697,101 IU urokinase (n=23)

Clinical success

Hemodynamic stabilization, improvement in pulmonary hypertension

and survival

SEATTLE II (n = 150)Massive (n=31) or submassive (n=119) with

RV/LV ratio > 0.9

t-PA 1mg/h/cath for a total of 24 mg

Change in RV/LV ratio

Major bleeding within 72 hours

Anticoagulation practices not

disclosed

PERFECT (n = 101)Clinical success

Massive PE24 of 28 patients(85.7%)

Submassive PE 71 of 73 patients(97.3%)

DeathMassive 4 (14%)

Submassive 2 (3%)

Pulmonary hypertension84.8 % showed improvement

pre, 51.2 mm Hg; post, 37.2 mm Hg; P <.0001

Low dose heparin with a goal of 40-60

seconds

SEATTLE II (n = 150)RV/LV ratio

1.55 at baseline to 1.13 at 6 hrs(p<0.0001)

PASP 51.4 mm Hg at baseline to 37.5 post

(p<0.0001)

Modified Miller Index 22.5 at baseline to 15.8 post

(p<0.0001)

PERFECT (n = 101)no major procedure-related

complications, major hemorrhages, or hemorrhagic

strokes

Minor bleeding 13 of 101 patients (12.9%)

Hospital LOS 8.23 days

No additional benefit from USAT

SEATTLE II (n = 150)Death

In hospital 2%, 30 day 2.7%

Hospital LOS 8.8 days

Major bleedingWithin 30 days 10%

More likely to occur in massive23% vs. 7%; p = 0.02

ICH0%

2017 ANNUAL MEETING

#FSHP2017Comparison of OptionsComparison of OptionsSystemic thrombolysis Efficacy Safety LOS CostPEITHO (2014)TOPCOAT (2014)MAPPET-3 (2002)TIPES (2010)

1.2-4.5% mortality

3.6-11.5%major bleeding risk

2-5% ICH

8-16 days

Half dose/safe dose 1.6-6% mortality

0-11% majorbleeding risk

0% ICH

2-3 days Goldhaber et al. (1993)MOPPETT (2013)Wang C et al. (2010)Interventional therapy 0-5.9%

mortality0 -10% major bleeding risk

0% ICH

8-9 daysULTIMA (2014)SEATTLE II (2015)PERFECT (2015)

8

Konstantinides S. N Engl J Med 2002; 347(15):1143-1150Sharifi M. Am J Cardiol. 2013;111:273–7. Kucher N, Circulation 2014;129:479-486Piazza G, J Am Coll Cardiol Intv 2015;8:1382-92Kuo WT, Chest 2015;148(3):667-673

KlineJA. J Thromb Haemost 2014; 12: 459–68.Becattini C. Thrombosis Research 2010;125:e82-e86Meyer G. N Engl J Med 2014;370;1402-11Sharifi M. Am J Cardiol. 2013;111:273–7. Goldhaber SZ. Chest 1994; 106; 725-726 Wang C. Chest 2010; 137(2):254-262

2017 ANNUAL MEETING

#FSHP2017ConclusionsConclusions• The use of thrombolysis in submassive PE remains highly controversial• Lack of mortality benefit has shifted approaches to evaluate

secondary outcomes• Methods to maximize therapeutic benefit while reducing risk

• Half dose or safe dose • Interventional therapy

• Therapeutic decisions may be based on patient attributes • Risk stratification PESI + biomarker• Interventional therapy centrally located, high risk

FSHP 2017 ANNUAL MEETING

Breaking it Down: An Evidence Based Update on ThrombolyticsBreaking it Down: An Evidence Based Update on ThrombolyticsJason Ferreira, Pharm.D., BCPS, BCCCPMedical ICU pharmacistUF Health Jacksonville

2017 ANNUAL MEETING

#FSHP2017References References • Tapson VF. Acute Pulmonary Embolism. N Engl J Med 2008;358:1037-52

• Prandoni P, Lensing AW, Prins MH, et al Prevelance of pulmonary embolism among patients hospitalized for syncope. N Engl J Med 2016;375:1524-31.

• Fengler BT, Brady WJ. Fibrinolytic therapy in pulmonary embolism: an evidence based treatment algorithm. American Journal of Emergency Medicine 2009;27:84-95

• Jaff MR, McMurtry MS, Archer SL, Cushman M, Goldbenberg N, Goldhaber SZ, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: A scientific statement from the American Heart Association. Circulation. 2011;123:1788-1830

• Goldhaber S, Visani L, DeRosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). The Lancet; Apr 24,1999; 353,9162;

• Konstantinides SV, Vicaut E, Danays T, et al. Impact of thrombolytic therapy on long term outcome of intermediate risk pulmonary embolism. J Am Coll Cardiol 2017;69:1536-44

• Sista AK, Horowitz JM, Goldhaber SZ. Four key questions surrounding thrombolytic therapy for submassive pulmonary embolism. Vascular medicine 2016;21(1):47-52

• KlineJA, Nordenholz KE, Courtney DM, et al. treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double blind, placebo-controlled randomized controlled trial. J Thromb Haemost 2014; 12: 459–68.

• Meyer G, Vicaut E, Danyas T, et al Fibrinolysis for patients with intermediate risk pulmonary embolism N Engl J Med 2014;370;1402-11

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2017 ANNUAL MEETING

#FSHP2017References References • Tsikouris JP, Tsikouris AP. A review of available fibrin specific thrombolytic agents used in acute myocardial

infarction. Pharmacotherapy 2001; 21(2):207-217

• Campbell J, Hilleman D. Recombinant Peptides in Thrombolysis. Semin Thromb Hemost 2010;36:529-536

• Kunadian V, Gibson CM. Recombinant tissue type plasminogen activators: time matters. Drugs of Today 2011;47(7):559-570

• Agnelli G, Becattini C. Acute Pulmonary Embolism. N Engl J Med 2010;363:266-74

• Wan S, Quinlan DJ, et al. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta analysis of the randomized controlled trials. Circulation 2004;110:744-9

• Jerjes-Sanchez C, Ramirez-Rivera A, et al. Streptokinase and heparin versus heparin alone in massive pulmonary embolism: a randomized controlled trial. J Thromb Thrombolysis 1995;2:227-9

• Konstantinides S, Geibel A, Heusel G, et al. Heparin Plus Alteplase Compared with heparin alone in patients with submassive pulmonary embolism (MAPPET-3) trial. N Engl J Med 2002; 347(15):1143-1150

• Becattini C. Agnelli G, Salvi A, et al. Bolus tenectaplase for right ventricular dysfunction in hemodynamically stable patients with pulmonary embolism(TIPES trial). Thrombosis Research 2010;125:e82-e86

• Mikkola KM, Patel SR. Increasing age is a major risk factor for hemorrhagic complications after pulmonary embolism thrombolysis. Am Heart J 1997;134:69-72.

• Simoons ML, Maggioni AP, et al. Individual risk assessment for intracranial hemorrhage during thrombolytic therapy. Lancet 1993; 342:1523-8.

• Kline JA, Steuerwald MT, Marchick MR, Hernandez-nino J and Rose GA. Prospective evaluation of right ventricular function and functional status 6 months after acute submassive pulmonary embolism: frequency of persistent or subsequent elevation in estimated pulmonary artery pressure. Chest 2009;136:1202-1210

2017 ANNUAL MEETING

#FSHP2017References References • Sharma G, Folland ED, McIntyre KM, Sasahara. Long-term benefit of thrombolytic therapy in patients with

pulmonary embolism. Vascular Medicine 2000;5:91-95

• Wang C, Zhai Z, Yang Y, et al. Efficacy and safety of Low Dose Recombinant Tissue-Type Plasminogen Activator for the Treatment of Acute Pulmonary Thromboembolism. Chest 2010; 137(2):254-262

• Goldhaber SZ, Feldstein ML, Sors H. Two Trials of Reduced Bolus Alteplase in the Treatment of Pulmonary Embolism: An Overview. Chest 1994; 106; 725-726

• Sharifi M, Bay C, Skrocki L, et al. Moderate pulmonary embolism treated with thrombolysis (from the ‘MOPETT’ Trial). Am J Cardiol. 2013;111:273–7.

• Ellias A, Mallett S, Daoud-Elias M, Poggi J, Clarke M. Prognostic models in acute pulmonary embolism: a systematic review and meta anlysis. BMJ open 2016;6:e010324. doi:10.1136/bmjopen-2015-010324

• Kucher N, Boekstegers P, Muller OJ, et al. Randomized controlled trial of ultrasound assisted catheter directed thrombolysis for acute intermediate risk pulmonary embolism. Circulation 2014;129:479-486

• Piazza G, Hohlfelder B, Jaff MR, et al. A prospective, single arm, multicenter trial of ultrasound facilitated catheter directed low dose fibrinolysis for acute massive and submassive pulmonary embolism, the SEATTLE II study. J Am Coll Cardiol Intv 2015;8:1382-92

• Kuo WT, Banerjee A, Kim PS, et al. Pulmonary embolism response to fragmentation embolectomy and catheter thrombolysis (PERFECT): initial results from a prospective multicenter registry. Chest 2015;148(3):667-673

• Sharifi M, Bay C, Schwartz F, Skrocki L. Safe-dose thrombolysis plus rivaroxibn for moderate and severe pulmonary embolism: Drip, drug, discharge. Clin Cardiol 2014;37(2):78-82