Role of Thrombolysis in Treatment of Pulmonary Embolism
Rajeeve K Rajput, Deepak Kumar
Apollo Hospital, New Delhi

Acute pulmonary embolism (PE) is a major cause of death associated with surgery, injury, and medical illnesses.   Pulmonary thrombo-embolism is responsible for up to 15% of all in-hospital deaths and accounts for 20 to 30% of deaths associated with pregnancy and delivery. Overall, the annual incidence of pulmonary embolism ranges between 23 and 69 cases per 100,000 population, (1) with an average case fatality rate within 2 weeks of diagnosis of approximately 11 %( 2) roughly accounting for at least 100,000 deaths each year. Pulmonary embolism is almost always due to venous thrombosis in deep veins of the calf, propagating into proximal veins from where they are more likely to embolize to lungs. The triad of hyper-coagulability, vascular stasis and local injury to the vessel wall is responsible for thrombus formation. Diagnosis of   PE   is based on clinical  suspicion , demonstration of thrombus  in leg veins and  in  pulmonary vasculature .The clinical symptoms , physical examination, routine tests like ECG , X Ray chest   are often  non specific  thus  requiring a high index of suspicion in high risk  populations . Various clinical scoring systems (3) (Fig 1) and diagnostic work up protocols have been proposed to improve the sensitivity and specificity of diagnosing PE.

Multidetector CT pulmonary angiography (4) is the most reliable modality to confirm diagnosis of PE. It is quick, specific, provides additional information regarding RV dilatation and Function

V/ Q scan may be helpful but is often non diagnostic; normal scan however rules out PE.  MRI may be used but does not detect thrombi in smaller pulmonary arteries.   Pulmonary angiography may be used   especially when a catheter based therapy is planned.  Demonstration of thrombus in leg veins by Ultrasound, contrast CT, MRI   or conventional venography may increase the diagnostic accuracy (5). D- Dimer assay may help in patients with low and intermediate probability of pulmonary embolism; patients with normal values do not require further tests or treatment (6).

The treatment  of PE depends on clinical  risk stratification  Table  1 .Presentation with shock , Hypotension  with out  shock  and normal blood pressure  with RV dialation / dysfunction   are high risk features associated  with increased  mortality  and morbidity . In-hospital mortality in PE patients with and without Echocardiographic RV dilatation has been found to be 18.4% and 5.7%, respectively (7). In another study Ribeiro et al. also reported a higher mortality in patients with PE and severe RVD; 14.3%   as compared to   7.9% in the overall population (8.)

The ICOPER registry reported a 2-week mortality of 15.9% in patients presenting with RVD in comparison with 8% in patients without RVD (9). In MAPPET 10% of patients with RVD died within 30 days as compared to 4.1% of patients without RVD (10). RVD is a common finding in

patients with acute PE and normal blood pressure. In a recent study patients with acute PE were classified according to the presence of RVD and hypotension; the short-term mortality and the incidence of PE-related shock in patients with normal BP and echo RVD was respectively 5% and 10%. None of the patients with normal BP and no RVD died or experienced PE-related shock.

Patients  with non high risk features should be initially  treated with rest and Heparin ;  Un-fractionated or low molecular weight heparin or Fondaparinux ;  followed by oral anticoagulation and addressing the precipitating factors (11,12) .
Patients with high risk features have a very high mortality and morbidity and require more aggressive treatment with prompt removal of thrombus from the pulmonary vasculature. Treatment with heparins and antiplatelets is associated with unacceptable high mortality in this subgroup. Mechanical removal of thrombus   using catheterization techniques with various types of devices has been tried with variable success rates. Pharmacological  dissolution  of the thrombus  with thrombolytic agents , similar  to clot lysis in  Acute Myocardial  Infarction has shown  good results in this high risk subgroup .
Thrombolytic agents (e.g., urokinase, streptokinase, and alteplase) rapidly dissolve thromboembolic obstruction and have favorable hemodynamic effects (13). The greatest benefit is observed when treatment is initiated within 48 hours after the onset of symptoms, but thrombolysis can still be effective in patients who have had symptoms for up to 14 days (14). A meta-analysis of five randomized trials that included patients with arterial hypotension or shock showed that thrombolysis effectively reduced the risk of death or recurrent pulmonary embolism (9.4%, vs. 19.0% with heparin alone; odds ratio, 0.45; 95% CI, 0.22 to 0.92
However, the benefits of thrombolysis in patients with pulmonary embolism who have normal blood pressure are less well established. Results from a randomized trial suggested that selected patients with evidence of right ventricular dysfunction and a low risk of bleeding may benefit from early thrombolysis. In this study, early treatment with alteplase plus heparin, as compared with heparin, reduced the need for emergency therapeutic measures during the hospital stay; however, no benefit was found with respect to in-hospital mortality.
Thrombolytic therapy carries a significant risk of bleeding. Pooled data from studies assessing various thrombolytic regimens showed a cumulative risk of major bleeding of 13 % and a 1.8% rate of intracranial or fatal hemorrhage (16). An overview of thrombolytic regimens for the treatment of pulmonary embolism is shown in Table 2. Data from head-to-head trials indicate that the approved thrombolytic agents are equivalent in terms of the clinical outcomes; regimens with shorter infusion periods are thus preferred. Direct infusion of thrombolytic agents through a catheter in the pulmonary artery has not been shown to offer any advantages over systemic intravenous thrombolysis(11)

Newer thrombolytic agents have been developed which can be administered as a bolus, have rapid onset of action and are at least as effective and as safe as reteplase .Tenectepalse is a genetically engineered variant of alteplase with slower plasma clearance, better fibrin specificity, and high resistance to plasminogen-activator inhibitor-1 (17). The  therapeutic dose can be administered  as single bolus in 5  minutes , thus making it an ideal  lytic agent for acute treatment in PE  .The safety and efficacy of   tenecteplase  in the  treatment of acute myocardial infarction has been well established in  ASSENT 2 trial  . This double-blind, randomised, controlled trial, done in 1021 hospitals,  assigned 16,949 patients with acute myocardial infarction of less than 6 hour  duration  to  rapid infusion of alteplase (< or = 100 mg) or single-bolus injection of tenecteplase (30-50 mg according to bodyweight).  The primary outcome was equivalence in all-cause mortality at 30 days. Rates of intracranial hemorrhage were similar (0.93% for tenecteplase and 0.94% for alteplase), but fewer non-cerebral bleeding complications (26.43 vs 28.95%, p=0.0003) and less need for blood transfusion (4.25 vs 5.49%, p=0.0002) were seen with tenecteplase (18).
With the proven safety profile and ease of administration as a single bolus agent in AMI, tenecteplase   seems to be the ideal thrombolytic agent for patients of acute pulmonary embolism.

There is no large randomized control trial of use of tenecteplase in PE .There are few case reports of which have shown promising results with tenecteplase. C  Melzar reported a study of   four patients with massive and sub-massive PE who were treated with weight-optimized dosing regimen of tenecteplase, administered as an intravenous bolus.  All patients’ experienced clinical improvement   in dyspnoea with regression of right ventricular enlargement was documented in three cases. Tenecteplase was well tolerated without any major bleeding complications (19). Kline JA et al published  data of 8  pts   of  PE treated  with  iv  tenecteplase  in emergency  department and showed favorable out come without  major bleeding  (20) .

A phase 2 double blind , multi center, randomized Italian study which aimed to enroll 180 patients with PE with normal blood pressure and RVD, in a double blind fashion, to receive Tenecteplase + UFH (90 patients) or Placebo + UFH (90 patients) was prematurely terminated (21).
An ongoing trial, PLEITHO (Pulmonary Embolism Thrombolysis Study) is currently recruiting patients with submassive PE, defined by normal blood pressure and RVD. This randomised double blind active control efficacy study shall compare efficacy and safety of single iv bolus teneteplase plus standard anticoagulation vs standard anticoagulation. Primary outcome measures include cinical composite endpoint of all-cause mortality or hemodynamic collapse within 7 days. This study aims to enroll 1000 patients and likely to be complete by November 2010 (22). The results of this large randomised study will answer the unresolved issue of utility of tenecteplase as thrombolytic agent in submassive PE.

Conclusions
. Thrombolysis reduces mortality and recurrence of PE in patients with massive pulmonary embolism. There is some evidence that thrombolysis is beneficial in submassive PE, however results of ongoing trials are awaited. With the proven safey, efficacy and unique mode of single bolus administration tenecteplase appears to be ideal thrombolytic agent in PE.

References
1. Silverstein MD,Heit JA,Mohar DN,Petterson TM,O’Fallon WM. Trends in the incidence of deep vein thrombosis and pulmonary embolism:a 25 year population based study.Arch Intern Med 1998;158:585- 593.

2. Goldhaber SZ,Visani L,De Rosa M.Acute pulmonary embolism:clinical outcomes in the International Cooperative Pulmonary Embolism Registry(ICOPER).Lancet 1999;353:1386-1389.

3. Wells PS,Anderson DR,Roger M,et al.Excluding pulmonary embolism at the bedside without diagnostic imaging:management of patients with suspected pulmonary emboli presenting to the emergency department by using a simple clinical model and D-dimer.Ann Intern Med 2001;135:98-107.

4. Stein PD,Fowler SE,Goodman LR,etal.Multidetector computed tomography for acute pulmonary embolism.N Engl J Med 2006;354:2317-2327.

5. Perrier A,Howath N,Didier D,etal.Performance of helical computed tomography in unselected outpatients with suspected pulmonary embolism.Ann Intern Med 2001:135;88-97.
6. Torbicki A,Perrier A,Konstantinides SV,etal.Guidelines on the diagnosis and management of Acute Pulmonary Embolism of Europian Society of Cardiology.Eur Heart J 2008;29;2276-2315.

7. .Schoepf UJ,KucherN,Kipmueller F,Quiroz R,etal.Right ventricular enlargement on chest computed tomography:apredictor of early death in acute pulmonary embolism.Circulation 2004;110:3276-3280.

8. American Heart Journal, Volume 134, Issue 3, Pages 479-487 A.Ribeiro, P.Lindmarker, A.Juhlin-Dannfelt, H.Johnsson, L.Jorfeld

9. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER) The Lancet, Volume 353, Issue 9162, Pages 1386-1389 S.Goldhaber, L.Visani, M.De Rosa

10. Konstantinides S, Geibel A, Olschewski M, Heinrich F, Grosser K, Rauber K, Iversen S, Redecker M, Kienast J, Just H, Kasper W. Impact of thrombolytic treatment on the prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry Circulation. 1997;96:882-888.

11. Kearon C,Kahn SR,Agnelli G,Goldhaber S,etal.Antithrombotic therapy for venous thrombolic disease:American college of chest physicians.Chest 2008;133:Suppl:454S-545S
12. Quinlan DJ,McQuillan A,Eikelbloom JW.Low molecular weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism:a meta-analysis of randomised controlle trials.Ann I ntern Med 2004;140:175-183.

13. Wan S,Quinlan DJ,Agnelli G,Eikenbloom JW.Thrombolysis compared with heparin for initial treatment of pulmonary embolism:a metaanalysis of the randomised controlled trials.Circulation 2004;110:744-749.

14. Daniels LB,Parker JA,Patel SR,Grodstein F,Goldhaber SZ.Relation of duration of synptoms with response to thrombolytic therapy in pulmonary embolism.Am J Cardiol 1997;80:184-188.

15. Konstantinides S,Geibel A,Heusel G,Heinrich F.Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism.N Engl Med 2002;347:1143-1150.

16. Konstantinides S,Marder VJ.Thrombolysis in Venous Thromboembolism Hemostatsis and Thrombosis basic Principles in clinical Practise 5 th Edition . Philadelphia Lippincott Williams and Wilkins 2006 1317-29

17. Keyt BA, Paoni NF, Refino CJ, et al. A faster-acting and more potent form of tissue plasminogen activator. Proc Natl Acad Sci USA. 1994;91(9):3670-3674.

18. Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators. Single bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double- blind randomised trial. Lancet. 1999;354:716-722.

19. Tenecteplase for the Treatment of Massive and Submassive Pulmonary Embolism Journal of Thrombosis and Thrombolysis, Journal of Thrombosis and Thrombolysis, 47-50

20. Tenecteplase to treat pulmonary embolism in the emergency department. - Kline JA - J Thrombolysis - 01-APR-2007; 23(2): 101-5

21. Tenecteplase Pulmonary Embolism Italian Study.www. clinicaltrials.gov/ct2/show/NCT00222651

22. PEITHO Pulmonary Embolism Thrombolysis Study www.clinicaltrials.gov/ct2/show/NCT00639743