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Three Part Question

In patients with [haemodynamically stable pulmonary embolism] does [thrombolytic therapy] improve [mortality and morbidity]?

Clinical Scenario

a patient presents with pleuritic chest pain, hypoxia and dyspnoea. A CT pulmonary angiogram confirms significant PE. The patient is haemodynamically stable but you are aware of the mortality and long-term sequelae associated with PE. Should you proceed to thrombolysis or anti-coagulate?

Search Strategy

1. MEDLINE (1950 to July week 1 2009)
2. EMBASE (1980 to July week 1 2009)
3. CINAHL
4. Cochrane database

1. pulmonary embolism.mp. or exp Pulmonary Embolism
2. pulmon$ embol$.mp.
3 thrombolytic therapy.mp. or exp Thrombolytic Therapy
4. 1 or 2
5. tissue plasminogen activator.mp. or exp Tissue Plasminogen Activator/ (14700)
6. fibrinolytic agents.mp. or exp Fibrinolytic Agents/ (129253)
7 exp Streptokinase/ or streptokinase.mp. (10505)
8 thrombolysis.m_titl. (5296)
9 8 or 6 or 3 or 7 or 5 (141792)
10 submassive.mp. [mp=title, original title, abstract, name of substance word, subject heading word] (302)
11 submassive.m_titl. (86)
12 11 or 10 (302)
13 'haemodynamically stable'.mp. [mp=title, original title, abstract, name of substance word, subject heading word] (316)
14 13 or 12 (617)
15 4 and 9 and 14 (94)
16 from 15 keep 1-94 (94)
17 15 and 4 and 9 and 14 (94)
18 (sub$ adj massive).mp. [mp=title, original title, abstract, name of substance word, subject heading word] (117)
19 18 or 13 or 12 (728)
20 4 and 19 and 9 (107)

Search Outcome

a total of 145 papers were found.
8 of these were relevant, studying the outcomes in only haemodynamically stable patients with PE treated with thrombolysis and heparin.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
PIOPED investigators 1990 USA	13 patients with PE and stable haemodynamics were randomised to rtPA (dose variable) plus unfractionated heparin(UFH) or UFH alone.	RCT	pulmonary perfusion, right heart haemodynamics, mortality, major bleeding	mortality 11% with thrombolysis vs 0% with heparin	trial powered for 50 but abandoned due to slow patient accession.
Levine et al 1990 USA	58 patients randomised to rtPA 0.6mg/kg bolus (n=33) + UFH or UFH alone (n=25). follow up period 7 days	RCT	mortality, V/Q reperfusion, major haemorrhage, PE recurrence	mortality 3% with rtPA vs 0 with heparin alone. >50% improvement in V/Q in 34.4% of rtPA and 12% heparin (p=0.026). no major bleeds or PE recurrence in either group.	small sample size randomisation and blinding methods unclear
Dalla-Volta et al 1992 Italy	36 patients radomised to alteplase 10mg + 90mg infusion + UFH (n=20) or UFH (n=16). follow up period 30 dyas.	RCT	mortality, lung perfusion, major haemorrhage, PE recurrence	mortality 10% with thrombolysis vs 5% with heparin. PE recurrence in 12.5% of heparin alone patients and 5% thrombolysed. major haemorrhage 15% with thrombolysis and 12.5% heparin.	small sample size
Goldhaber 1993 USA	101 patients randomised to 100mg infusion of alteplase + UFH (n= 46) or UFH alone (n=55). follow up period 14 days.	RCT	mortality, major haemorrhage, PE recurrence, right ventricular function	mortality 0 with thrombolysis and 3.6% in heparin group. no major bleeding events. PE recurrence 0 with thrombolysis vs 9% UFH. RVF improved in 39% of thrombolysed patients and 17% UFH (p=0.005)	treatment not blinded.
Konstantinides 1997 Germany	719 patients assigned to thrombolysis (n=169) or heparin alone (n=550). followed up period 30 days.	multicentre cohort study	mortality, major haemorrhage, PE recurrence	mortality 4.7% in thrombolysed patients and 11.1% with heparin alone. PE recurrence 7.7% with thrombolysis and 18.7% with heparin. major haemorrhage in 15.6% thrombolysed and 7.8% heparinised patients.	not an RCT so treatment at the discretion of treating physician. thrombolysed group as a whole tended to be younger (p=0.003) and have fewer co-morbidities such as CCF and COPD which are independent predictors of mortality in PE. heterogeneous thrombolytic agents and UFH or LMWH
Hamel 2001 France	128 patients selected from total of 153. 64 selected for study from each group. matched for pre-treatment characteristics. follow up period 10 days	cohort	mortality, major haemorrhage, PE recurrence	mortality 6.5% in thrombolysed group and 0 in heparin. PE recurrence 4.7% in each group. major bleeding in 15.6% of thrombolysed and 0 heparin patients.	treatment at discretion of treating physician but patient groups well matched. thrombolytic agent used heterogeneous.
Konstantinides 2002 Germany	256 patients randomised to 100mg bolus alteplase + 90mg infusion + UFH (n=118) or UFH alone (n=138). follow up period 30 days.	RCT	mortality, major haemorrhage, PE recurrence, treatment escaltion	mortality 3.4% thrombolysed patients vs 2.2% with heparin. major haemorrhage in 0.8% thrombolysis group vs 3.6% heparin. PE recurrence 3.4% thrombolysed and 2.95 heparin.	patients able to be unblinded at physicians' discretion if felt to be clinically deteriorating.

Comment(s)

There is insufficient evidence to recommend the administration of thrombolytic therapy to patients with haemodynamically stable pulmonary embolism. Risks associated with thrombolytic therapy are not insignificant. Patients treated with heparin tend to recannalise within 5-7 days, and the head start offered by thrombolysis has not been proven to confer enough improvement in mortality and morbidity to overcome the risks. Patients with evidence of right heart failure at diagnosis have been demonstrated to have a higher mortality and may benefit from thrombolysis but insufficient evidence exists at present.

Clinical Bottom Line

thrombolysis is not indicated in haemodynamically stable pulmonary embolism.

References

1. PIOPED investigators Tissue plasminogen activator for the treatment of acute pulmonary embolism. chest 1990; 97: 528-33
2. Levine M A randomized trial of a single bolus dosage regimen of recombinant tissue plasminogen activator in patients with acute pulmonary embolism. chest 1990; 98: 1473-79.
3. Dalla-Volta S PAIMS 2: Alteplase combines with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen Activator Italian Multicentre Study 2. journal of the american colege of cardiologists 1992; 20 (3): 520-6
4. Goldhaber S Alteplase versus heparin in acute pulmonary embolism: randomized trial assessing right-ventricular function and pulmonary perfusion. Lancet 1993; 341: 507-11.
5. Konstantinides S Association between thrombolytic treatment and the prognosis of haemodynamically stable patients with major pulmonary embolism. Circulation 1997; 96: 882-888
6. Hamel E Thrombolysis or heparin therapy in massive pulmonary embolism with right ventricular dilation. Chest 2001; 120: 120-125.
7. Konstantinides S Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. MAPPET-3. new england journal of medicine 2002; 347: 1143-1150
8. Zhang Y Thrombolytic therapy with urokinase for pulmonary embolism in patients with stable haemodynamics. Medical Science Monitor 2007; 13(1): 20-23.