Thrombolytics for Pulmonary Embolism

two in two daysChristopher Partyka8th April 2014

Thrombolytics for PECan we alter outcomes ?!?

Scary statisticTwo thirds of patients who die of PE do so within an hour of hospital presentation

more scary statistics...~10% of non-traumatic sudden deaths

1 in 2 arrive in PEA/asystole

MASSIVE

~5% of PEs

58% 90 daymortality

SUBMASSIVE

~40% of PEs

22% 90 day mortality

MINOR

~55% of PEs

<1% 90 daymortality

Massive PE

Overt right ventricular failure

Persistent systemic arterial hypotension

SBP < 90mmHg for 15mins or more

Shock

Pulselessness~5% of casesHigh mortality

Death within hours...

Submassive PE

A population at risk

RV dysfunction without hypotension

Dilatation or hypokinesis on ECHO

Dilatation on CT

↑ Troponin

↑ Pro-BNP

Right heart “cripples”Chronic pulmonary HTN

Poor functionality upon DC

Submassive PERV:LV > 0.9 predicts mortality

OR 2.53 [95%CI 1.17-5.50]

Persistent RV dysfunction at discharge

4x mortality !!

8x recurrent PE

44% have chronic PHT at 1 year

Troponin elevation predicts mortality

OR 5.90 [95%CI 2.68-12.95]

Why we should care !!

Bust some clots ?!

Pros:

Rapid resolution of symptoms

Stabilise cardiorespiratory function

Reduce RV damage

Improve exercise tolerance

Increase probability of survival

Avoid vasopressors

Avoid intubation

We only need a 33% ↓

Bust some clots ?!

Cons:

Disabling or fatal haemorrhage (incl. ICH)

Blood transfusions

Unnecessary intervention (incl. surgery)

Increased hospital LOSRisk of ICH ~ 2-3%

Risk of major bleeding ~ 22%

The evidence...

Thrombolytics for PEWhat is accepted practice then ?!

Thrombolysis:

first line treatment for massive PE [B]

may be instituted on clinical grounds alone if cardiac arrest is imminent [B]

a 50 mg bolus of alteplase is recommended [C]

not used as first line treatment in non-massive PE [B]

Thrombolysis:

first line treatment for massive PE [B]

may be instituted on clinical grounds alone if cardiac arrest is imminent [B]

a 50 mg bolus of alteplase is recommended [C]

not used as first line treatment in non-massive PE [B]

“major haemorrhage is twice that of heparin”

Thrombolysis:

reasonable for massive PE w/ acceptable bleeding risk [B]

considered for submassive PE w/ adverse prognosis & low risk of bleeding [C]

NOT for low-risk PE [B] or undifferentiated cardiac arrest [B]

Thrombolytics for PEBlind application doesn’t work !!!

~70% of OHCA result from AMI or PE

Thrombolytics during CPR may improve survival

DB RCT

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 359;25 www.nejm.org december 18, 2008 2651

original article

Thrombolysis during Resuscitation for Out-of-Hospital Cardiac Arrest

Bernd W. Böttiger, M.D., Hans-Richard Arntz, M.D., Douglas A. Chamberlain, M.D., Erich Bluhmki, Ph.D., Ann Belmans, M.Sc.,

Thierry Danays, M.D., Pierre A. Carli, M.D., Jennifer A. Adgey, M.D., Christoph Bode, M.D., and Volker Wenzel, M.D., M.Sc.,

for the TROICA Trial Investigators and the European Resuscitation Council Study Group*

From the University of Cologne, Cologne, and the University of Heidelberg, Heidel-berg — both in Germany (B.W.B.); Charité, Benjamin Franklin Medical Center, Berlin (H.-R.A.); the Prehospital Emergency Re-search Unit, School of Medicine, Cardiff University, Cardiff, United Kingdom (D.A.C.); Boehringer Ingelheim, Biberach, Germany (E.B.); the Biostatistical Center, Catholic University of Leuven, Leuven, Belgium (A.B.); Boehringer Ingelheim, Reims, France (T.D.); Service d’Aide Médicale d’Urgence de Paris, Hôpital Necker–Enfants Mal-ades, Paris (P.A.C.); the Regional Medical Cardiology Centre, Royal Victoria Hospital, Belfast, United Kingdom (J.A.A.); Albert-Ludwig-University, Freiburg, Germany (C.B.); and Innsbruck Medical University, Innsbruck, Austria (V.W.). Address reprint requests to Dr. Böttiger at the Depart-ment of Anesthesiology and Postopera-tive Intensive Care Medicine, University of Cologne, Kerpener Str. 62, Cologne D-50937, Germany, or at [email protected].

*The investigators in the Thrombolysis in Cardiac Arrest (TROICA) trial are listed in the Appendix.

N Engl J Med 2008;359:2651-62.Copyright © 2008 Massachusetts Medical Society.

A BS TR AC T

BACKGROUNDApproximately 70% of persons who have an out-of-hospital cardiac arrest have under-lying acute myocardial infarction or pulmonary embolism. Therefore, thrombolysis during cardiopulmonary resuscitation may improve survival.

METHODSIn a double-blind, multicenter trial, we randomly assigned adult patients with wit-nessed out-of-hospital cardiac arrest to receive tenecteplase or placebo during cardio-pulmonary resuscitation. Adjunctive heparin or aspirin was not used. The primary end point was 30-day survival; the secondary end points were hospital admission, return of spontaneous circulation, 24-hour survival, survival to hospital discharge, and neurologic outcome.

RESULTSAfter blinded review of data from the first 443 patients, the data and safety moni-toring board recommended discontinuation of enrollment of asystolic patients be-cause of low survival, and the protocol was amended. Subsequently, the trial was terminated prematurely for futility after enrolling a total of 1050 patients. Tenec-teplase was administered to 525 patients and placebo to 525 patients; the two treat-ment groups had similar clinical profiles. We did not detect any significant differ-ences between tenecteplase and placebo in the primary end point of 30-day survival (14.7% vs. 17.0%; P = 0.36; relative risk, 0.87; 95% confidence interval, 0.65 to 1.15) or in the secondary end points of hospital admission (53.5% vs. 55.0%, P = 0.67), return of spontaneous circulation (55.0% vs. 54.6%, P = 0.96), 24-hour survival (30.6% vs. 33.3%, P = 0.39), survival to hospital discharge (15.1% vs. 17.5%, P = 0.33), or neuro-logic outcome (P = 0.69). There were more intracranial hemorrhages in the tenecte-plase group.

CONCLUSIONSWhen tenecteplase was used without adjunctive antithrombotic therapy during ad-vanced life support for out-of-hospital cardiac arrest, we did not detect an improvement in outcome, in comparison with placebo. (ClinicalTrials.gov number, NCT00157261.)

The New England Journal of Medicine Downloaded from nejm.org on January 22, 2014. For personal use only. No other uses without permission.

Copyright © 2008 Massachusetts Medical Society. All rights reserved.

NEJM 2008; 359:2651-62

Tenecteplase vs Placebo during cardiac-arrest



original article








A BS TR AC T







NEJM 2008; 359:2651-62 T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 359;25 www.nejm.org december 18, 20082656

20, 2006, yielded conditional power for a success-ful completion of the study of less than 1%. The data and safety monitoring board therefore rec-ommended suspension of the trial on March 23, 2006, and the executive committee immediately directed all investigators to stop enrolling patients. At a final meeting on July 4, 2006, on the basis of the results for all 1050 patients who had under-gone randomization, the data and safety monitor-ing board recommended that the trial be stopped. The final decision by the executive committee to follow the recommendation of the data and safety monitoring board was made on July 15, 2006.

Baseline characteristics are reported as means ±SD, medians with interquartile ranges, or per-centages, as appropriate. Analysis of the primary end point was performed with the log-rank test. All secondary end points were analyzed with a continuity-corrected chi-square test. Nine prespec-ified subgroup analyses16 and one post hoc sub-group analysis were performed. Missing end-point

data were imputed according to a worst-case sce-nario. All analyses were performed with the use of SAS software, version 8.02.

R esult s

PATIENT CHARACTERISTICSFrom January 24, 2004, to March 23, 2006, a total of 1050 patients were enrolled in the trial. Of these, 525 were assigned to tenecteplase and 525 to pla-cebo. Fifty-eight patients (29 assigned to tenecte-plase and 29 assigned to placebo) did not receive the study drug; in 33 of these 58 patients (18 as-signed to receive tenecteplase and 15 assigned to receive placebo), the return of spontaneous circu-lation had already occurred; in 19 (8 and 11, re-spectively), exclusion criteria were detected after randomization; and in 6 (3 and 3, respectively), the study drug was not administered for other, mis-cellaneous reasons.

The two trial groups were similar in almost all

Table!4.!Outcomes.

Outcome!Tenecteplase!Group

(N!=!525)Placebo!Group

(N!=!525)Relative!Risk

(95%!CI) P!Value

no./total no. (%)

Primary end point

30-Day survival 77/525 (14.7) 89/525 (17.0) 0.87 (0.65–1.15) 0.36

Secondary end points

Return of spontaneous circulation 283/515 (55.0) 279/511 (54.6) 1.01 (0.90–1.13) 0.96

Hospital admission 281/525 (53.5) 289/525 (55.0) 0.97 (0.87–1.09) 0.67

24-Hr survival 158/517 (30.6) 171/514 (33.3) 0.92 (0.77–1.10) 0.39

Survival to hospital discharge 78/517 (15.1) 90/514 (17.5) 0.86 (0.65 –1.14) 0.33

Neurologic outcome* 0.69

Good cerebral performance 41/86 (47.7) 45/96 (46.9) 1.02 (0.75–1.38)

Moderate cerebral disability 13/86 (15.1) 9/96 (9.4) 1.12 (0.88–1.42)

Severe cerebral disability 10/86 (11.6) 16/96 (16.7) 1.02 (0.86–1.21)

Coma 14/86 (16.3) 18/96 (18.8) 0.99 (0.90–1.08)

Brain death 8/86 (9.3) 8/96 (8.3) 1.00

Safety end points

Symptomatic intracranial hemorrhage 4/518 (0.8) 0/514 8.93 (0.48–165.45) 0.13

Any intracranial hemorrhage 14/518 (2.7) 2/514 (0.4) 6.95 (1.59–30.41) 0.006

Major nonintracranial hemorrhage 40/517 (7.7) 33/514 (6.4) 1.21 (0.77–1.88) 0.48

Ischemic stroke 4/518 (0.8) 3/514 (0.6) 1.32 (0.30–5.88) 1.00

* Neurologic outcome is measured by cerebral performance category; categories range from 1 to 5, with 1 indicating good cerebral perfor-mance and 5 indicating brain death. The relative risks and associated 95% confidence intervals (CIs) are based on cumulative rates.





original article








A BS TR AC T







NEJM 2008; 359:2651-62 T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 359;25 www.nejm.org december 18, 20082656

20, 2006, yielded conditional power for a success-ful completion of the study of less than 1%. The data and safety monitoring board therefore rec-ommended suspension of the trial on March 23, 2006, and the executive committee immediately directed all investigators to stop enrolling patients. At a final meeting on July 4, 2006, on the basis of the results for all 1050 patients who had under-gone randomization, the data and safety monitor-ing board recommended that the trial be stopped. The final decision by the executive committee to follow the recommendation of the data and safety monitoring board was made on July 15, 2006.

Baseline characteristics are reported as means ±SD, medians with interquartile ranges, or per-centages, as appropriate. Analysis of the primary end point was performed with the log-rank test. All secondary end points were analyzed with a continuity-corrected chi-square test. Nine prespec-ified subgroup analyses16 and one post hoc sub-group analysis were performed. Missing end-point

data were imputed according to a worst-case sce-nario. All analyses were performed with the use of SAS software, version 8.02.

R esult s

PATIENT CHARACTERISTICSFrom January 24, 2004, to March 23, 2006, a total of 1050 patients were enrolled in the trial. Of these, 525 were assigned to tenecteplase and 525 to pla-cebo. Fifty-eight patients (29 assigned to tenecte-plase and 29 assigned to placebo) did not receive the study drug; in 33 of these 58 patients (18 as-signed to receive tenecteplase and 15 assigned to receive placebo), the return of spontaneous circu-lation had already occurred; in 19 (8 and 11, re-spectively), exclusion criteria were detected after randomization; and in 6 (3 and 3, respectively), the study drug was not administered for other, mis-cellaneous reasons.

The two trial groups were similar in almost all

Table!4.!Outcomes.

Outcome!Tenecteplase!Group

(N!=!525)Placebo!Group

(N!=!525)Relative!Risk

(95%!CI) P!Value

no./total no. (%)

Primary end point

30-Day survival 77/525 (14.7) 89/525 (17.0) 0.87 (0.65–1.15) 0.36


Return of spontaneous circulation 283/515 (55.0) 279/511 (54.6) 1.01 (0.90–1.13) 0.96

Hospital admission 281/525 (53.5) 289/525 (55.0) 0.97 (0.87–1.09) 0.67

24-Hr survival 158/517 (30.6) 171/514 (33.3) 0.92 (0.77–1.10) 0.39

Survival to hospital discharge 78/517 (15.1) 90/514 (17.5) 0.86 (0.65 –1.14) 0.33

Neurologic outcome* 0.69

Good cerebral performance 41/86 (47.7) 45/96 (46.9) 1.02 (0.75–1.38)

Moderate cerebral disability 13/86 (15.1) 9/96 (9.4) 1.12 (0.88–1.42)

Severe cerebral disability 10/86 (11.6) 16/96 (16.7) 1.02 (0.86–1.21)

Coma 14/86 (16.3) 18/96 (18.8) 0.99 (0.90–1.08)

Brain death 8/86 (9.3) 8/96 (8.3) 1.00

Safety end points

Symptomatic intracranial hemorrhage 4/518 (0.8) 0/514 8.93 (0.48–165.45) 0.13

Any intracranial hemorrhage 14/518 (2.7) 2/514 (0.4) 6.95 (1.59–30.41) 0.006

Major nonintracranial hemorrhage 40/517 (7.7) 33/514 (6.4) 1.21 (0.77–1.88) 0.48

Ischemic stroke 4/518 (0.8) 3/514 (0.6) 1.32 (0.30–5.88) 1.00

* Neurologic outcome is measured by cerebral performance category; categories range from 1 to 5, with 1 indicating good cerebral perfor-mance and 5 indicating brain death. The relative risks and associated 95% confidence intervals (CIs) are based on cumulative rates.



No survival benefit

No increase in ROSC

Increased rates of ICH in those who survived

MAPPET-3 Trial

N Engl J Med, Vol. 347, No. 15

·

October 10, 2002

·

www.nejm.org

·

1143

ALTEPLASE IN PULMONARY EMBOLISM

HEPARIN PLUS ALTEPLASE COMPARED WITH HEPARIN ALONE IN PATIENTS WITH SUBMASSIVE PULMONARY EMBOLISM

S

TAVROS

K

ONSTANTINIDES

, M.D., A

NNETTE

G

EIBEL

, M.D., G

ERHARD

H

EUSEL

, P

H

.D., F

RITZ

H

EINRICH

, M.D.,

AND

W

OLFGANG

K

ASPER

, M.D.,

FOR

THE

M

ANAGEMENT

S

TRATEGIES

AND

P

ROGNOSIS

OF

P

ULMONARY

E

MBOLISM

-3 T

RIAL

I

NVESTIGATORS

*

A

BSTRACT

Background

The use of thrombolytic agents in thetreatment of hemodynamically stable patients withacute submassive pulmonary embolism remains con-troversial.

Methods

We conducted a study of patients withacute pulmonary embolism and pulmonary hyper-tension or right ventricular dysfunction but withoutarterial hypotension or shock. The patients were ran-domly assigned in double-blind fashion to receiveheparin plus 100 mg of alteplase or heparin plus pla-cebo over a period of two hours. The primary endpoint was in-hospital death or clinical deteriorationrequiring an escalation of treatment, which was de-fined as catecholamine infusion, secondary throm-bolysis, endotracheal intubation, cardiopulmonary re-suscitation, or emergency surgical embolectomy orthrombus fragmentation by catheter.

Results

Of 256 patients enrolled, 118 were random-ly assigned to receive heparin plus alteplase and 138to receive heparin plus placebo. The incidence of theprimary end point was significantly higher in the hep-arin-plus-placebo group than in the heparin-plus-alteplase group (P=0.006), and the probability of 30-day event-free survival (according to Kaplan–Meieranalysis) was higher in the heparin-plus-alteplasegroup (P=0.005). This difference was due to the high-er incidence of treatment escalation in the heparin-plus-placebo group (24.6 percent vs. 10.2 percent,P=0.004), since mortality was low in both groups(3.4 percent in the heparin-plus-alteplase group and2.2 percent in the heparin-plus-placebo group, P=0.71). Treatment with heparin plus placebo was as-sociated with almost three times the risk of death ortreatment escalation that was associated with hepa-rin plus alteplase (P=0.006). No fatal bleeding or cer-ebral bleeding occurred in patients receiving heparinplus alteplase.

Conclusions

When given in conjunction with hep-arin, alteplase can improve the clinical course of stablepatients who have acute submassive pulmonary em-bolism and can prevent clinical deterioration requiringthe escalation of treatment during the hospital stay.(N Engl J Med 2002;347:1143-50.)

Copyright © 2002 Massachusetts Medical Society.

From the Department of Cardiology and Pulmonary Medicine, Georg-August-Universität, Göttingen (S.K.); the Department of Cardiology andAngiology, Albert-Ludwigs-Universität, Freiburg (A.G.); Boehringer Ingel-heim Pharma, Ingelheim (G.H.); Krankenhaus Bruchsal, Bruchsal (F.H.); andDepartment of Internal Medicine, St. Josefs Hospital, Wiesbaden (W.K.) —all in Germany. Address reprint requests to Dr. Konstantinides at the Depart-ment of Cardiology and Pulmonary Medicine, Georg-August-Universität Göt-tingen, Robert Koch Str. 40, Göttingen, D-37075 Germany, or at [email protected].

*The investigators are listed in the Appendix.

HROMBOLYSIS is an established treatmentfor patients with acute massive pulmonaryembolism and hemodynamic instability orcardiogenic shock.

1

In contrast, the effect ofthrombolytic agents on the outcome of hemodynam-ically stable patients who have submassive pulmonaryembolism has been debated for decades.

2,3

Several fac-tors have contributed to the ongoing controversy: thelack of a large, randomized study assessing clinical endpoints,

4

the risk of serious hemorrhage associated withthrombolytic therapy,

1,5-7

and the fact that patients’hemodynamic status may gradually improve with hep-arin therapy alone.

8,9

The clinical data currently available underscore theneed to identify patients in whom thrombolysis mayhave a favorable risk–benefit ratio. Studies based ontwo large, multicenter registries reported that patientswith right ventricular dysfunction due to pulmonaryembolism had increased rates of in-hospital death, evenin the absence of arterial hypotension or shock.

5,10

These findings are in accord with the results of earlyexperimental studies on the pathophysiology of venousthromboembolism.

11

Data from one of these registriesalso suggested that early thrombolytic therapy mightfavorably affect the prognosis of these patients.

12

Wetherefore undertook a randomized, placebo-controlledtrial to compare the effects of treatment with hepa-rin plus alteplase with the effects of heparin plus pla-cebo on the outcome of patients with acute submas-sive pulmonary embolism. We focused on patientswith pulmonary hypertension, right ventricular dys-function, or both, but we excluded those with hemo-dynamic instability.

METHODS

Study Population

To be included in the trial, patients with acute pulmonary em-bolism had to fulfill at least one of the following criteria, which weredefined a priori: echocardiographically detected right ventricular

T



NEJM 2002;347:1143-50

MAPPET-3 Trial


·

October 10, 2002

·

www.nejm.org

·

1143

ALTEPLASE IN PULMONARY EMBOLISM

HEPARIN PLUS ALTEPLASE COMPARED WITH HEPARIN ALONE IN PATIENTS WITH SUBMASSIVE PULMONARY EMBOLISM

S

TAVROS

K

ONSTANTINIDES

, M.D., A

NNETTE

G

EIBEL

, M.D., G

ERHARD

H

EUSEL

, P

H

.D., F

RITZ

H

EINRICH

, M.D.,

AND

W

OLFGANG

K

ASPER

, M.D.,

FOR

THE

M

ANAGEMENT

S

TRATEGIES

AND

P

ROGNOSIS

OF

P

ULMONARY

E

MBOLISM

-3 T

RIAL

I

NVESTIGATORS

*

A

BSTRACT

Background

The use of thrombolytic agents in thetreatment of hemodynamically stable patients withacute submassive pulmonary embolism remains con-troversial.

Methods

We conducted a study of patients withacute pulmonary embolism and pulmonary hyper-tension or right ventricular dysfunction but withoutarterial hypotension or shock. The patients were ran-domly assigned in double-blind fashion to receiveheparin plus 100 mg of alteplase or heparin plus pla-cebo over a period of two hours. The primary endpoint was in-hospital death or clinical deteriorationrequiring an escalation of treatment, which was de-fined as catecholamine infusion, secondary throm-bolysis, endotracheal intubation, cardiopulmonary re-suscitation, or emergency surgical embolectomy orthrombus fragmentation by catheter.

Results

Of 256 patients enrolled, 118 were random-ly assigned to receive heparin plus alteplase and 138to receive heparin plus placebo. The incidence of theprimary end point was significantly higher in the hep-arin-plus-placebo group than in the heparin-plus-alteplase group (P=0.006), and the probability of 30-day event-free survival (according to Kaplan–Meieranalysis) was higher in the heparin-plus-alteplasegroup (P=0.005). This difference was due to the high-er incidence of treatment escalation in the heparin-plus-placebo group (24.6 percent vs. 10.2 percent,P=0.004), since mortality was low in both groups(3.4 percent in the heparin-plus-alteplase group and2.2 percent in the heparin-plus-placebo group, P=0.71). Treatment with heparin plus placebo was as-sociated with almost three times the risk of death ortreatment escalation that was associated with hepa-rin plus alteplase (P=0.006). No fatal bleeding or cer-ebral bleeding occurred in patients receiving heparinplus alteplase.

Conclusions

When given in conjunction with hep-arin, alteplase can improve the clinical course of stablepatients who have acute submassive pulmonary em-bolism and can prevent clinical deterioration requiringthe escalation of treatment during the hospital stay.(N Engl J Med 2002;347:1143-50.)

Copyright © 2002 Massachusetts Medical Society.

From the Department of Cardiology and Pulmonary Medicine, Georg-August-Universität, Göttingen (S.K.); the Department of Cardiology andAngiology, Albert-Ludwigs-Universität, Freiburg (A.G.); Boehringer Ingel-heim Pharma, Ingelheim (G.H.); Krankenhaus Bruchsal, Bruchsal (F.H.); andDepartment of Internal Medicine, St. Josefs Hospital, Wiesbaden (W.K.) —all in Germany. Address reprint requests to Dr. Konstantinides at the Depart-ment of Cardiology and Pulmonary Medicine, Georg-August-Universität Göt-tingen, Robert Koch Str. 40, Göttingen, D-37075 Germany, or at [email protected].

*The investigators are listed in the Appendix.

HROMBOLYSIS is an established treatmentfor patients with acute massive pulmonaryembolism and hemodynamic instability orcardiogenic shock.

1

In contrast, the effect ofthrombolytic agents on the outcome of hemodynam-ically stable patients who have submassive pulmonaryembolism has been debated for decades.

2,3

Several fac-tors have contributed to the ongoing controversy: thelack of a large, randomized study assessing clinical endpoints,

4

the risk of serious hemorrhage associated withthrombolytic therapy,

1,5-7

and the fact that patients’hemodynamic status may gradually improve with hep-arin therapy alone.

8,9

The clinical data currently available underscore theneed to identify patients in whom thrombolysis mayhave a favorable risk–benefit ratio. Studies based ontwo large, multicenter registries reported that patientswith right ventricular dysfunction due to pulmonaryembolism had increased rates of in-hospital death, evenin the absence of arterial hypotension or shock.

5,10

These findings are in accord with the results of earlyexperimental studies on the pathophysiology of venousthromboembolism.

11

Data from one of these registriesalso suggested that early thrombolytic therapy mightfavorably affect the prognosis of these patients.

12

Wetherefore undertook a randomized, placebo-controlledtrial to compare the effects of treatment with hepa-rin plus alteplase with the effects of heparin plus pla-cebo on the outcome of patients with acute submas-sive pulmonary embolism. We focused on patientswith pulmonary hypertension, right ventricular dys-function, or both, but we excluded those with hemo-dynamic instability.

METHODS

Study Population

To be included in the trial, patients with acute pulmonary em-bolism had to fulfill at least one of the following criteria, which weredefined a priori: echocardiographically detected right ventricular

T



NEJM 2002;347:1143-50

MAPPET-3 Trial

DB RCT

Acute PE with RV strain- ECG- ECHO- CT

Heparin plus 100mg alteplasevs

Heparin plus placebo

MAPPET-3 Trial

DB RCT

Acute PE with RV strain- ECG- ECHO- CT

No difference shown for in-hospital mortality(3.4% vs 2.2%; p=0.71)

More cases of clinical deterioration requiring therapy escalation in heparin-alone group

(24.6% vs 10.2%; p=0.004)

Only 31% had ECHO confirmationof RV strain !!

MAPPET-3 Trial

1146

·


·

October 10, 2002

·

www.nejm.org

The New England Journal of Medicine

stay was 16.7±8.4 days (range, 2 to 70). The mortal-ity rate was low in both treatment groups. Four pa-tients in the heparin-plus-alteplase group died, twofrom pulmonary embolism and two from underlyingdisease. Three patients in the heparin-plus-placebogroup died, two from pulmonary embolism and onefrom a bleeding complication. Although the mortalityrate in the two groups was similar, the rate of escala-tion of treatment because of clinical deterioration wasmuch higher in the heparin-plus-placebo group thanin the heparin-plus-alteplase group. For example, sec-ondary (rescue) thrombolysis was performed rough-ly three times as often in the heparin-plus-placebogroup as in the heparin-plus-alteplase group (Table 2).In the heparin-plus-placebo group, the indications forsecondary thrombolysis were cardiogenic shock (in4 patients), arterial hypotension requiring catechola-mine infusion (in 4), and worsening symptoms andrespiratory failure (in 24 patients, 3 of whom under-went endotracheal intubation and mechanical ventila-tion). In the heparin-plus-alteplase group, nine pa-tients underwent additional thrombolysis, one becauseof arterial hypotension and the remaining eight be-cause of worsening symptoms; one of the latter pa-tients underwent endotracheal intubation). Overall,

the incidence of the primary end point (death or es-calation of treatment) was significantly greater in theheparin-plus-placebo group than in the heparin-plus-alteplase group (34 patients [24.6 percent] vs. 13 pa-tients [11.0 percent], P=0.006).

In accord with these data, the probability of 30-day event-free survival according to Kaplan–Meieranalysis was significantly higher in the group of pa-tients treated with heparin plus alteplase than in thosetreated with heparin plus placebo (P=0.005 by thelog-rank test) (Fig. 1). Further analysis with use ofthe proportional-hazards model confirmed that treat-ment with heparin plus placebo predicted an unfavor-able in-hospital outcome: the relative risk of the pri-mary end point with heparin plus placebo as comparedwith heparin plus alteplase was 2.63 (P=0.006) (Ta-ble 3). As shown in Figure 2, the favorable outcomeof the patients assigned to heparin plus alteplase wasnot due to greater effectiveness of heparin anticoag-ulation in this group than in the other group, sincethe activated partial-thromboplastin time reached sim-ilar levels in the two treatment groups between 12and 48 hours after randomization. Of the other base-line variables tested in the proportional-hazards mod-el, age older than 70 years, female sex, and the pres-

*The numbers shown are based on calculations for the intention-to-treat population.†P values were calculated with the use of Fisher’s exact test (two-sided).‡Recurrence of pulmonary embolism had to be confirmed by ventilation–perfusion lung scanning,

spiral computed tomography, or pulmonary angiography.§Major bleeding was defined as fatal bleeding, hemorrhagic stroke, or a drop in the hemoglobin

concentration by at least 4 g per deciliter, with or without the need for red-cell transfusion.¶Hemorrhagic or ischemic stroke had to be confirmed by computed tomography or magnetic res-

onance imaging.

T

ABLE

2.

I

N

-H

OSPITAL

C

LINICAL

E

VENTS

.*

E

VENT

H

EPARIN

PLUS

A

LTEPLASE

(N=118)

H

EPARIN

PLUS

P

LACEBO

(N=138) P V

ALUE

†

no. (%)

Primary end point

13 (11.0) 34 (24.6) 0.006Death from all causes 4 (3.4) 3 (2.2) 0.71Escalation of treatment 12 (10.2) 34 (24.6) 0.004

Catecholamine infusion (for persistent hypotension or shock)

3 (2.5) 8 (5.8) 0.33

Secondary thrombolysis 9 (7.6) 32 (23.2) 0.001Endotracheal intubation 3 (2.5) 3 (2.2) 0.85Cardiopulmonary resuscitation 0 1 (0.7) 1.0Embolectomy or thrombus fragmentation 0 1 (0.7) 1.0


Recurrent pulmonary embolism‡ 4 (3.4) 4 (2.9) 0.89Major bleeding§ 1 (0.8) 5 (3.6) 0.29

Fatal bleeding 0 1 (0.7) 1.0Hemorrhagic stroke¶ 0 0 —

Ischemic stroke¶ 0 1 (0.7) 1.0



The “MOPPET” trial

Moderate Pulmonary Embolism Treated With Thrombolysis(from the “MOPETT” Trial)

Mohsen Shari!, MDa,b,*, Curt Bay, PhDb, Laura Skrocki, DOa, Farnoosh Rahimi, MDa,and Mahshid Mehdipour, DMDa,b, “MOPETT” Investigators

The role of low-dose thrombolysis in the reduction of pulmonary artery pressure inmoderate pulmonary embolism (PE) has not been investigated. Because the lungs are verysensitive to thrombolysis, we postulated that effective and safe thrombolysis might beachieved by a lower dose of tissue plasminogen activator. The purpose of the present studywas to evaluate the role of this “safe dose” thrombolysis in the reduction of pulmonaryartery pressure in moderate PE. During a 22-month period, 121 patients with moderate PEwere randomized to receive a “safe dose” of tissue plasminogen activator plus anti-coagulation (thrombolysis group [TG], n [ 61 patients) or anticoagulation alone (controlgroup [CG], n[ 60). The primary end points consisted of pulmonary hypertension and thecomposite end point of pulmonary hypertension and recurrent PE at 28 months. Pulmonaryhypertension and the composite end point developed in 9 of 58 patients (16%) in the TGand 32 of 56 patients (57%) in the CG (p <0.001) and 9 of 58 patients (16%) in the TG and35 of 56 patients (63%) in the CG (p <0.001), respectively. The secondary end points weretotal mortality, the duration of hospital stay, bleeding at the index hospitalization, recurrentPE, and the combination of mortality and recurrent PE. The duration of hospitalization was2.2 – 0.5 days in the TG and 4.9 – 0.8 days in the CG (p <0.001). The combination of deathplus recurrent PE was 1 (1.6%) in TG and 6 (10%) in the CG (p [ 0.0489). No bleedingoccurred in any group, and despite a positive trend in favor of a “safe dose” thrombolysis,no signi!cant difference was noted in the rate of individual outcomes of death and recurrentPE when assessed independently. In conclusion, the results from the present prospectiverandomized trial suggests that “safe dose” thrombolysis is safe and effective in the treat-ment of moderate PE, with a signi!cant immediate reduction in the pulmonary arterypressure that was maintained at 28 months. ! 2013 Elsevier Inc. All rights reserved. (AmJ Cardiol 2013;111:273e277)

Thrombolysis is an effective tool in the treatment ofmassive pulmonary embolism (PE).1,2 It has also been rec-ommended for “submassive PE,” in which hemodynamicstability is present but with right ventricular (RV) enlarge-ment or hypokinesia or the elevation of biomarkers of RVinjury.1e5 The dreaded complication of thrombolysis isintracerebral hemorrhage, which has been noted in 0.7% to6.4% of patients receiving thrombolysis.6,7 This frequency,albeit low, has caused a reluctance in the use of thrombol-ysis for symptomatic PE without hemodynamic instability.Our experience with percutaneous endovenous interventionfor deep venous thrombosis has suggested an exquisitelyfavorable pulmonary response to low-dose thrombolysis.8

The lungs are uniquely sensitive to thrombolysis, becausethey are the only organ receiving the entire cardiac output.Furthermore, they are the point of convergence for the entiremolecules of the thrombolytic agent, no matter throughwhich vein the drug is administered. It is therefore intriguingto postulate that a lower dose of the thrombolytic drug might

be effective in PE, with the additional bene!t of enhancingits safety pro!le. No data are available on peripheral intra-venous administration of low-dose thrombolysis for“moderate” PE in the reduction of pulmonary artery pres-sures after 2 years. The present study was, therefore,undertaken to assess the effects of low-dose tissue plas-minogen activator (tPA) on pulmonary artery systolicpressure in patients with “moderate” PE at 28 months.

Methods

The Moderate Pulmonary Embolism Treated withThrombolysis trial was a prospective, controlled, random-ized, single-center open study that enrolled 121 adult patientswith symptomatic “moderate” PE. All patients providedwritten informed consent, and the institutional review boardapproved the study protocol.

Adult patients presenting with signs and symptomssuggestive of PE plus imaging documentation on computedtomographic angiography or ventilation/perfusion scanningwere potentially eligible for the study. “Moderate” PE wasde!ned as the presence of signs and symptoms of PE pluscomputed tomographic pulmonary angiographic involve-ment of >70% involvement of thrombus in !2 lobar or leftor right main pulmonary arteries (Figure 1) or by a highprobability ventilation/perfusion scan showing ventilation/perfusion mismatch in !2 lobes. Interpretation of the

aArizona Cardiovascular Consultants, Mesa, Arizona; and bA.T. StillUniversity, Mesa, Arizona. Manuscript received August 24, 2012; revisedmanuscript received and accepted September 18, 2012.

See page 277 for disclosure information.*Corresponding author: Tel: (480) 924-0006; fax: (480) 924-0579.E-mail address: [email protected] (M. Shari!).

0002-9149/12/$ - see front matter ! 2013 Elsevier Inc. All rights reserved. www.ajconline.orghttp://dx.doi.org/10.1016/j.amjcard.2012.09.027

AM J Cardiol 2013;111:273e277

Half dose t-PA for submassive (moderate) PE


Single-centre, randomised

“half dose” t-PA vs control [no placebo]

Unwell patients w/ moderate PE

Anatomical defn of ‘submassive’

ECHO not required prior to enrolment


Theory:

PE is exquisitely sensitive to 'lytics

the lungs see 100% of the circulation

Brain ~ 15%

Myocardium ~5%

lower dose → lower complications


Primary endpoints:

Pulmonary HTN

Recurrent PE


Primary endpoints:

Pulmonary HTN

Recurrent PE

Pulmonary HTN at 28 months:

16% vs 57%, p<0.001


Secondary endpoints:

Total mortality

Hospital LOS

Bleeding

Recurrent PE


Secondary endpoints:

Total mortality

Hospital LOS

Bleeding

Recurrent PE

Benefits:↓ recurrent PE - 0% vs 5%, p=0.08

↓ hospital LOS - 2.2 vs 4.9 days, p<0.001

Indifferences:Total mortality

Bleeding - none in either group

PEITHO trial

American Heart Journal, 163(1), 33–38.e1.

PEITHO trial

Prospective, international, MC, DB, RCT

Tenecteplase vs placebo

+ standard anticoagulation

1006 normotensive patients w/ confirmed PE +

abnormal RV on ECHO or CT and

elevated troponin

PEITHO trial

been reached for 2 consecutive days; alternatively, it ispossible to switch patients from intravenous UFHinfusion to subcutaneous injections of LMWH orfondaparinux at a weight-adjusted dosage 48 hours orlater after randomization.

OutcomesThe primary efficacy outcome is the composite of

death from any cause or hemodynamic collapse within7 days of randomization. Hemodynamic collapse isdefined as at least 1 of the following: (i) the need forcardiopulmonary resuscitation; (ii) systolic blood pres-sure b90 mm Hg for at least 15 minutes, or drop ofsystolic blood pressure by at least 40 mm Hg for at least15 minutes, with signs of end-organ hypoperfusion(cold extremities, or urinary output b30 mL/h, ormental confusion); (iii) the need for catecholamines(except for dopamine at a rate of b5 !g kg!1 min!1) tomaintain adequate organ perfusion and a systolic bloodpressure of N90 mm Hg. The primary efficacy outcomeof PEITHO is, thus, different from that of a previouslarge thrombolysis trial (death or escalation of treat-ment, mainly consisting of secondary thrombolysis).23

The secondary outcomes are as follows: (1) death fromany cause within 7 days, (2) hemodynamic collapse (asdefined above) within 7 days, (3) imaging-confirmedsymptomatic recurrence of PE within 7 days, and (4)death within 30 days. Confirmation of recurrent PE

requires a new filling defect demonstrated by pulmo-nary angiography or spiral computed tomography, or anew perfusion defect by lung scan indicating highprobability of PE. There is no routine surveillance forasymptomatic recurrent venous thromboembolism.Safety outcomes include the following: (1) ischemic or

hemorrhagic stroke within 7 days, (2) other major (ie,moderate or severe) bleeding within 7 days, and (3)serious adverse events (SAEs) within 30 days. Moderatebleeding is defined as a bleeding episode requiring bloodtransfusion(s) but one that is not considered lifethreatening and does not lead to hemodynamic compro-mise requiring emergency fluid replacement, inotropicsupport, or interventional/surgical treatment. Severebleeding is defined as an episode that leads to hemody-namic compromise requiring emergency intervention(as administration of fluids and/or blood products,inotropic support, or surgical treatment), or is life-threatening, or fatal.

Long-term follow-upThe patient's vital status will be recorded 6 months

after randomization. This may be done by an appoint-ment at the clinic or, in case of death, by contact (viatelephone or mail) with the patient's family or physician.The follow-up can be done between days 180 and 210,but the status must be given for day 180 afterrandomization. If follow-up is done earlier, a repeated

Table I. Inclusion and exclusion criteria

Inclusion criteria Exclusion criteria

(1) Age 18 y (1) Hemodynamic collapse at presentation!!(2) Acute PE (first symptoms 15 d or less before randomization) confirmed by

lung scan, or a positive computed tomographic pulmonary angiogram,or a positive selective pulmonary angiogram

(2) Known significant bleeding risk

(3) RV dysfunction confirmed by echocardiography or spiral computedtomography of the chest

(3) Administration of a thrombolytic agent in the previous 4 d

Echocardiography (!1 criterion)

(4) Vena cava filter insertion or pulmonary thrombectomy in the previous 4 d

• RV end-diastolic diameter N30 mm (parasternal long axis or short axis)

(5) Uncontrolled hypertension (systolic BP N180 mm Hg and/or diastolic BPN110 mm Hg at randomization)

• Right/left ventricular end-diastolic diameter N0.9(apical or subcostal 4-chamber view)

(6) Treatment with an investigational drug under another study protocol inthe previous 7 d or longer, according to local requirements

• Hypokinesis of RV-free wall (any view)

(7) Previous enrollment in this study

• Tricuspid regurgitant jet velocity N2.6 m/s

(8) Known hypersensitivity to tenecteplase, alteplase, UFH, or any of theexcipients

Computed tomography(9) Pregnancy, lactation, or parturition within the previous 30 d; women ofchildbearing age must have a negative pregnancy test or use a medicallyaccepted method of birth control• Right/left short-axis diameter ratio N0.9 (transverse plane)(10) Known coagulation disorder (including use of vitamin K antagonistsand platelet count b100,000/mm3)

(4) Myocardial injury confirmed by a positive troponin I or T test result! (11) Any other condition that the investigator feels would place the patient atincreased risk if the investigational therapy were administered

BP denotes blood pressure.!Cutoff levels for defining elevating troponin I or T levels are defined by the Department of Clinical Chemistry at each participating site.!!At least 1 of the following: (i) the need for cardiopulmonary resuscitation; (ii) systolic blood pressure b90 mm Hg for at least 15 minutes, or a drop of systolic blood pressure by atleast 40 mm Hg for at least 15 minutes, with signs of end-organ hypoperfusion (cold extremities, urinary output b30 mL/h, or mental confusion); and (iii) the need for catecholamines(except for dopamine at a rate of "5 !g kg#1 min#1) to maintain adequate organ perfusion and a systolic blood pressure of N90 mm Hg.

The Steering Committee 35American Heart JournalVolume 163, Number 1

PEITHO trial

contact with the patient must be made on or after day180. Recorded data include the following: (1) in case ofdeath, the date and primary cause of death; (2) if thepatient is alive, the functional status and severity ofdyspnea using the New York Heart Association scale; and(3) echocardiographic parameters including estimatedsystolic pulmonary artery pressure and persistent RVdysfunction (based on the criteria listed in Table I).

Statistical analysisThe PEITHO trial is a prospective, multicenter,

international, randomized (1:1), double-blind, parallelgroup comparison. The aim is to demonstrate thesuperiority of tenecteplase over placebo with regard tothe primary composite end point, that is, death orhemodynamic collapse at 7 days. Null and alternative

hypotheses are as follows: H0: 7-day-death-hemcoltenect =7-day-death-hemcolplacebo vsH1: 7day-death-hemcoltenect!7day-death-hemcolplacebo (where hemcol stands for he-modynamic collapse, and tenect for tenecteplase). Themain analysis will be based on the intention-to-treat (ITT)population. In addition, an explanatory analysis (perprotocol) of all patients randomized and treated withoutmajor protocol violations/deviations will be carried out.Analysis on the primary and secondary end point(s) willbe carried out using a 2-sided !2 test on proportions. The95% CI on the odds ratio will be presented. Survival statusduring the 30-day follow-up will be analyzed showingKaplan-Meier curves, and treatment differences will becompared by means of log-rank test. Subgroup analysiswill be carried out for sex, age, and country. Potentiallyimportant prognostic factors for efficacy and safety willbe explored and used as covariates in relative risk analysisby logistic regression or the Cox model. Serious adverseevents will be tabulated per treatment group andanalyzed using the !2 test. Continuous safety monitoring(blinded) will also be done by the Data and SafetyMonitoring Board (DSMB), as explained below.Interim analyses are planned after recruitment of 25%,

50%, and 75% of the total number of patients. Theseanalyses are made to allow sample size reassessment orearly discontinuation of the trial because of efficacy orfutility. For these reasons, the "-spending functions

Figure 1

Confirmed acute

Ecom

es

acutesymptomatic

PE

Absence of

TNK §

DOUBLE omes

, SAE

dary

Out

c hemodynamic

collapse* UFH infusion ‡

ow-u

p

<2 h

UFH, LMWH or Fondaparinux

R

DOUBLE BLIND

VKA

nray

Out

o

me,

Sec

onConfirmed RV dysfunction + myocardial

injury** -term

Fol

lo

Placebo §

Seco

ry O

utco

m

UFH infusion ‡UFH, LMWH or Fondaparinux

Long

-

Prim

a

VKAUFH bolus i.v. †

Day 2 Day 7 Day 30 Day 180

Flow diagram of the Pulmonary Embolism International Thrombolysis trial. RV indicates right ventricular (dysfunction); TNK, tenecteplase;VKA, vitamin K antagonists. *As defined in Table I; **criteria defined in Table I; †at a dosage of 80 IU/kg of body weight; ‡initial infusion rate,18 IU/kg/h; §the dosing regimen for tenecteplase (or placebo) is shown in Table II.

Table II. Tenecteplase dosing regimen

Weight (kg) Dose (mg) Dose (Units) Volume (mL)

b60 30 6000 6!60 to b70 35 7000 7!70 to b80 40 8000 8!80 to b90 45 9000 9!90 50 10,000 10

36 The Steering CommitteeAmerican Heart Journal

January 2012

PEITHO trial

Primary outcome

Death or

Haemodynamic collapse =

CPR

SBP < 90 for ≥15mins

End-organ hypo perfusion

Vasopressor requirement

within 7 days...

PEITHO trial

Primary outcome

Death or

Haemodynamic collapse =

CPR

SBP < 90 for ≥15mins

End-organ hypo perfusion

Vasopressor requirement

Primary Outcomet-PA 2.6% vs Placebo 5.6%, p=0.015

RRR 54%

HD collapse t-PA 1.6% vs Placebo 5.0%, p=0.002esp. hypotension & vasopressor req.

No difference in 7-day mortality.

PEITHO trialSafety outcomes

Ischaemic or haemorrhagic stroke in 7 days

Other major bleeding = Fatal bleeding

Blood transfusion req'd

Inotropic support req'd

Emergent surgical intervention

PEITHO trialSafety outcomes

Ischaemic or haemorrhagic stroke in 7 days

Other major bleeding = Fatal bleeding

Blood transfusion req'd

Inotropic support req'd

Emergent surgical intervention

Increased risk of major & minor bleeding.

MAJOR: 6.3% vs 1.5%, p<0.001MINOR: 32.6% vs 8.6%, p<0.001

Stroke: 2.4% vs 0.2%, p=0.003

PEITHO No difference in 30-day mortality.

Finally; the MOPPET crewreturn in 2014...

Prospective, observational study.

98 consecutive patients with moderate to severe PE

“safe-dose” t-PA + heparin followed by rivaroxaban

ECHO followed for pulmonary HTN

Address for correspondence:Mohsen Sharifi, MD,Arizona Cardiovascular Consultantsand Vein Clinic, 3850 E. BaselineRoad, Building 1, Suite 102, Mesa, [email protected]

Clinical Investigations

Safe-Dose Thrombolysis Plus Rivaroxaban forModerate and Severe Pulmonary Embolism:Drip, Drug, and DischargeMohsen Sharifi, MD; Curt Bay, PhD; Frederic Schwartz, DO; Laura Skrocki, DOArizona Cardiovascular Consultants and Vein Clinic (Sharifi, Skrocki), Mesa, Arizona; A. T. StillUniversity (Sharifi, Bay, Schwartz), Mesa, Arizona

Background: Thrombolysis, though very effective, has not been embraced as routine therapy for symptomaticpulmonary embolism (PE) except in very severe cases. Rivaroxaban recently has been approved for thetreatment of venous thromboembolism (VTE). There are no data on the combined use of thrombolysis andrivaroxaban in PE.Hypothesis: ‘‘Safe dose’’ thrombolysis (SDT) plus new oral anticoagulants are expected to become anappealing, safe and effective approach in the treatment of moderate and severe PE in the near future, therebydrastically reducing hospitalization time.Methods: Over a 12-monthperiod, 98 consecutive patientswith symptomatic PEwere treatedby a combinationof SDT and rivaroxaban. The SDT was started in parallel with unfractionated heparin and given in 2 hours.Heparin was given for a total of 24 hours and rivaroxaban started at 15 or 20 mg daily 2 hours after terminationof heparin infusion.Results: There was no bleeding due to SDT. Recurrent VTE occurred in 3 patients who had been switched towarfarin. No patient on rivaroxaban developed VTE. Two patients died of cancer at a mean follow-up of 12 ± 2months. The pulmonary artery systolic pressure dropped from 52.8 ± 3.9 mm Hg before to 32 ± 4.4 mm Hgwithin 36 hours of SDT (P < 0.001). The duration of hospitalization for patients presenting primarily for PE was1.9 ± 0.2 days.Conclusions: ‘‘Safe dose’’ thrombolysis plus rivaroxaban is highly safe and effective in the treatment ofmoderate and severe PE, leading to favorable early and intermediate-term outcomes and early discharge.

IntroductionOver the last few years, new oral anticoagulants havebeen introduced that can replace vitamin K antagonistsin patients with pulmonary embolism (PE).1,2 The trialsdescribing these agents have uniformly excluded patientsreceiving thrombolysis. Though very effective, thrombolysishas not been embraced as routine therapy for symptomaticPE except in very severe cases. Even then, it has beenunderutilized in the real world for fear of bleeding,specifically the dreaded complication of intracerebralhemorrhage (ICH), which, for tissue plasminogen activator(tPA), has varied between 0.7% and 6.4%.3,4 Recently weintroduced the concept of ‘‘safe dose’’ thrombolysis (SDT),in which half the dose of tPA is given in conjunctionwith a modified dose of parenteral anticoagulation.5 Thisapproach has been highly safe and effective in the treatmentof moderate PE. Rivaroxaban is now approved in the UnitedStates for the treatment of venous thromboembolism (VTE).The combination of thrombolysis and rivaroxaban has

The authors have no funding, financial relationships, or conflictsof interest to disclose.

not been previously reported. This study describes ourexperience with the combination of SDT and rivaroxabanfor the treatment of moderate and severe PE.

MethodsOver a period of 12 months beginning in January 2012, 98consecutive patients with symptomatic PE were treated byour group with a combination of SDT and rivaroxaban. Theuse of rivaroxaban was off-label for most of the durationof this study, until it was approved by the US Food andDrug Administration for this indication in November 2012.This study was conducted in accordance with the amendedDeclaration of Helsinki. Written informed consent wasobtained from all patients, and the study was approvedby the institutional review board of A.T. Still University.

All patients had !3 new signs and symptoms: chest pain,tachypnea (resting respiratory rate !22/min), tachycardia(resting heart rate !90/min), dyspnea, oxygen desaturation(resting PO2 <95%), or elevated jugular venous pressure(!10 cm H2O). The onset of symptoms occurred withina mean of 7 ± 3 days (range, 1 day–6 weeks). Diagnosisof PE was made by objective testing with a computed

78 Clin. Cardiol. 37, 2, 78–82 (2014)Published online in Wiley Online Library (wileyonlinelibrary.com)DOI:10.1002/clc.22216 ! 2013 Wiley Periodicals, Inc.

Received: August 9, 2013Accepted with revision: August 31, 2013

Clin. Cardiol. 37(2) 78–82 (2014)












Clin. Cardiol. 37(2) 78–82 (2014)

Table 1. Clinical Characteristics of Patients

Variable Patients, N = 98

Men 47 (48)

Age, y 56 ± 10

Weight, kg 81 ± 11

BMI 28 ± 3

Previous or concomitant disease

Hypertension 54 (55)

DM 34 (35)

Cardiovascular 32 (33)

CAD 12 (12)

LVEF <40% 5 (5)

Valvular disease 5 (5)

Dysrhythmias 8 (8)

Other 4 (4)

Hypercholesterolemiaa 41 (42)

Pulmonary 30 (31)

COPD 20 (20)

Asthma 5 (5)

Malignancy 4 (4)

Sleep apnea 7 (7)

Renal 10 (10)

Current smoker 35 (36)

Unprovoked PE 54 (55)

Estrogen therapy 8 (8)

Cancer

Active 15 (15)

History 6 (6)

Known prothrombotic state 7 (7)

Previous VTE 16 (16)

Concomitant DVT 52 (53)

D-dimer elevation 87 of 87 (100)

TnI elevation 52 of 85 (61)

BNP elevation 59 of 80 (74)

RV enlargement 44 of 90 (49)

RV hypokinesia 21 of 90 (23)

Abbreviations: BMI, body mass index; BNP, brain natriuretic peptide;CAD, coronary artery disease; COPD, chronic obstructive pulmonarydisease; DM, diabetes mellitus; DVT, deep venous thrombosis;LVEF, left ventricular ejection fraction; PE, pulmonary embolism; RV,right ventricle; SD, standard deviation; TnI, troponin I; VTE, venousthromboembolism.Data are presented as n (%) or mean ± SD.aHypercholesterolemia indicates total cholesterol >200 mg/dL.

Figure 1. Box plot demonstrating pulmonary artery systolic pressuresupon initial measurement, within 36 hours of safe-dose thrombolysis, andat 6 months. Total number of patients with complete data = 88. Each ofthe 3 pairwise comparisons was significant (P < 0.001).

1.9 ± 0.2 days. This included 12 of 14 patients with severePE and 6 of 8 patients with severe PE who were hypotensiveon admission.

DiscussionThe results demonstrated that a combination of SDTand rivaroxaban is safe and effective in the treatmentof moderate and severe PE. It resulted in a rapiddecrease in PASP, improvement in clinical status, and earlydischarge. Recurrent VTE did not occur in patients receivingrivaroxaban and was only noted in patients receivingwarfarin. Two of these patients had cancer and 1 hada subtherapeutic international normalized ratio. It is wellestablished that warfarin failure is present in a large minorityof patients with cancer, with recurrent VTE developing inas many as 17% at 6 months.6 The bleeding incidents thatoccurred after discharge were not related to thrombolysisand were noted months later, when rivaroxaban waschanged to warfarin or when drug interaction occurredin a patient on additional dual antiplatelet therapy.

In the current study, and based on our experiencewith SDT, we have not witnessed any bleeding with thetPA dose used.5 Until recently, all existing trials usingperipheral venous access have uniformly used full dosesof thrombolytic agents. In the recent Pulmonary EmbolismThrombolysis Study (PEITHO), of the 506 patients whowere randomized to receive full-dose tenecteplase andheparin, minor and major bleeding occurred in 32.6%and 6.3% of the patients, respectively, including ICH,which occurred in 10 patients.7 The frequency of ICHwas 10! greater than that seen in the control group.7The results from a multicenter registry reported a major-bleeding rate of 21.9% in patients with major PE whoreceived full-dose thrombolysis, as compared with 7.8%receiving standard therapy.8 The International CooperativePulmonary Embolism Registry reported a 3% incidenceof ICH.9 In a retrospective review of data from 1998 to

80 Clin. Cardiol. 37, 2, 78–82 (2014)M. Sharifi et al: Thrombolysis plus rivaroxaban in PEPublished online in Wiley Online Library (wileyonlinelibrary.com)DOI:10.1002/clc.22216 ! 2013 Wiley Periodicals, Inc.












Clin. Cardiol. 37(2) 78–82 (2014)

No significant major or minor bleeding1x psoas haematoma1x gross haematuria

3 recurrent VTE [on warfarin]2 had cancer

Hospital LOS 1.9 ± 0.2 days

now we are enlightened...... back to our tales !!

Health & Medicine

Thrombolytics for Pulmonary Embolism