Review Article

Effectiveness of Tenecteplase Compared with Streptokinase and Heparin in the Treatment of Pulmonary Embolism of Varied Severity: A Retrospective Analysis

Ashish Agrawal1*, Shibnath kamila1, Aditya Donepudi1 and Rajendra Premchand2
1Department of Pharmacy, Bharat Institute of Technology, India
2Department of Cardiology, Krishna Institute of Medical Science, India


*Corresponding author: Ashish Agrawal, Bharat Institute of Technology, Hyderabad


Published: 12 Sep, 2017
Cite this article as: Agrawal A, kamila S, Donepudi A, Premchand R. Effectiveness of Tenecteplase Compared with Streptokinase and Heparin in the Treatment of Pulmonary Embolism of Varied Severity: A Retrospective Analysis. Ann Pharmacol Pharm. 2017; 2(17): 1091.

Abstract

Background: Thrombolytics are recommended in high risk patients with massive pulmonary embolism (PE). However, clinical practice seems to be far different and questions related to its utility in lesser severe patients remain subject of investigation. The objective of this retrospective study was to compare the efficacy and safety of tenecteplase with streptokinase and heparin.
Method: A total of 103 patients (tenecteplase: 62, streptokinase: 17, heparin: 24) diagnosed with PE (massive: 33[32.04%], submassive: 50[48.54%] and minor: 20[19.42%]) were included.
Results: Mean age was 50.04 years and major risk factors were immobilization due to hospitalization, history of deep vein thrombosis and diabetes. Common clinical symptoms of dyspnoea, right ventricular dysfunction and cough were found in 94.17, 81.55 and 77.67% patients, respectively. Between treatment and day 7 death occurred in 4.84, 5.88 and 8.33% patients in the tenecteplase, streptokinase and heparin group, respectively. The difference between treatment group was nonsignificant (p>0.05). All treatment have shown significant alleviation in the dyspnoea and heart rate (p<0.05). Significant (p<0.05) increase in the oxygen saturation was seen and it was markedly higher in the tenecteplase treated patients compared with the streptokinase and heparin. By day 7, there was 100% resolution of right bundle branch block only in the tenecteplase group. No intracranial bleeding or fatal bleeding episode was found in either group.
Conclusion: Tenecteplase was found to be effective in patients with PE irrespective of their clinical status and no major adverse events were noted.
Keywords: Thrombolytics; Pulmonary embolism; Tenecteplase; Heparin; Streptokinase


Introduction

Pulmonary embolism (PE) is a well-recognised common life threatening condition that is often difficult to detect. It is the most serious clinical presentation of venous thromboembolism and in majority of cases is the consequence of deep vein thrombosis [1]. Direct obstruction or occlusion of the pulmonary arteries and release of potent vasoconstrictors leads to quick rise in pulmonary vascular resistance. Due to this right ventricular (RV) contractile function is compromised and ensues its failure. This vicious cycle of cardiogenic shock is augmented by concomitant hypoxia, which inevitably leads to cardiovascular collapse and death [2,3].
The global incidence of PE is estimated to be 60- 70 per 100,000 of the general population and ranks third among the most common types of cardiovascular disease [4,5]. The mortality rate is 8-10% in treated patient and is as high as 25-30% in untreated patients [6]. Nearly 25% of patients die within the first hours of presentation and the actual figures can be even higher as patients who die before diagnosis usually do not get accounted [7]. Associated with significant morbidity and mortality, early diagnosis and timely treatment is of paramount importance to ensure the highest quality of care.
Appropriate treatment regimen can be best selected using risk stratification primarily by assessing hemodynamic impact, extent of PE, the patient’s clinical status and potential risks of the therapy [5]. Depending on PE presentation i.e. submassive (25%-50% obstruction), massive (>50% obstruction) or minor, initial treatment is primarily focused on restoring adequate blood flow through the pulmonary bed reversing RV failure and preventing PE recurrence [8]. Anticoagulation is an effective treatment and heparin is known to reduces both mortality and the incidence of recurrent PE. Although anticoagulants do not directly dissolve pre-existing clot, they prevent clot propagation and indirectly decrease clot burden by allowing endogenous fibrinolytic activity to dissolve existing thromboemboli. The rate at which this process occurs is variable and in many patients resolution is incomplete after several months. Thrombolytic therapy (streptokinase, urokinase, alteplase and tenecteplase) on the other hand, with its ability to produce rapid clot lysis offers an effective alternative and result in faster improvement in pulmonary perfusion, hemodynamic alterations, gas exchange with lesser incidence of recurrent PE. It also has shown to improve survival, especially in patients with high risk PE [9,10].
Tenecteplase is a modified form of human tissue plasminogen activator (tPA) that binds to fibrin and converts plasminogen to plasmin. It has three amino acid substitutions, which decrease plasma clearance, increase fibrin specificity and resistance to plasminogen activator inhibitor-1 (PAI-1). The modifications to tenecteplase allow the drug to be administered as a single intravenous bolus over 5 seconds [11,12].
Despite the critical nature of PE, to date fewer randomized clinical trials comparing thrombolytic agents versus heparin are conducted. Further literature search did not reveal any study comparing tenecteplase with streptokinase and heparin. Comparative studies with use of these agents are very limited and if available, the sample size is small. Thrombolytics are recommended in high risk patients with massive PE, its utility in lesser severe patients remain subject of investigation. All these conditions influenced us to conduct a study on tenecteplase comparing it with streptokinase and heparin in managing PE. The objective of the present study was to compare the efficacy and safety of tenecteplase with streptokinase and heparin.


Method

Anticoagulation with unfractionated and low molecular weight heparin has shown to improve outcome in pulmonary embolism [1]. Thrombolytic therapy has a potential to produce faster thrombolysis, improve hemo- dynamic instability and eliminate the venous thrombi [2]. Despite the approval of streptokinase, urokinase and alte- plase for thromolysis in PE, the efficacy of these thromo- lytics remain unclear due to the high mortality associated with this condition and lack of large randomized controlled trials [3,4]. Tenecteplase is a third generation thrombolytic with longer plasma half-life, better fibrin specificity, and higher resistance to inhibition by plasminogen-activator than alteplase [5].
This was a retrospective study conducted at Krishna Institute of Medical Sciences (KIMS) Hospital, Hyderabad, India. The protocol was approved by the Ethics Committee of KIMS and the study was conducted in accordance with the Declaration of Helsinki. Data of all hospitalized patients > 18 years of age diagnosed with PE from January 2008 to December 2014 and treated with tenecteplase, stretopkinase or heparin were included for analysis. The patients were diagnosed to have PE if there was evidence of thrombus as documented by CT pulmonary angiogram with or without D-dimer testing.
The exclusion criteria included patients with active visceral bleeding or spontaneous intracranial haemorrhage or those with a history of cardiopulmonary resuscitation, chronic pulmonary hypertension or severe COPD, patients with minimally controlled severe hypertension or diabetic hemorrhagic retinopathy and pregnant patients.


Assessment

All patients were followed for 180 days. Patient’s baseline data such as mean, age, gender, weight, disease characteristics, predisposing factors, etc was collected from their records. Patients with confirmed diagnosis of PE were classified as massive if there was evidence of hemodynamic compromise (defined as systolic BP <90 mmHg) and as submassive if there was right ventricular dysfunction on echocardiography with no hemodynamic compromise. Patients without any evidence of these features were labelled as minor PE cases.
The primary efficacy outcome was death from any cause within 7 days of treatment. The secondary outcome included death within 180 days, changes in prognostic factors after the therapy such as dyspnoea, blood pressure, heart rate, right bundle branch block (RBBB) and oxygen saturation (SaO2) at 7 days and 180 days.
Safety was assessed by evaluating adverse outcome especially bleeding complications.


Statistical Analysis

Baseline characteristics of patients are described according to treatment received. Continuous variables are summarized using descriptive statistics, i.e. number of subjects, mean, and standard deviation (SD). Qualitative variables are summarized by frequency and percentage. Student's t, Chi square or Fisher's exact tests were used to measure the association between clinical variables and the endpoint. Fisher exact test was used if there were more than 20% of cells with an expected value of <5 in a table.


Results

Demographic and baseline characteristics
A total of 103 patients diagnosed with pulmonary embolism were identified and included for analysis into the study. Their mean age was 50.04 years. Majority of the patients were males 66 (64.08%). The major predisposing factors were immobilization as a result of hospitalization, history of DVT and diabetes (Table 1). The most common clinical symptoms were dyspnoea (94.17%) followed by right ventricular dysfunction (81.55%) and cough (77.67%). Massive, submassive and minor PE was diagnosed in 33 (32.04%), 50 (48.54%) and 20 (19.42%) patients, respectively. All patients were treated with tenecteplase, streptokinase and heparin. Details baseline characteristics of the patients according to treatment group are presented in Table 1.
Primary efficacy parameter
Death: Between treatment and day 7 data, death occurred in 3 (4.84%) patients in the tenecteplase group as compared with 1 (5.88%) in the streptokinase group and 2 (8.33%) in the heparin group. By day 180, 6 (9.67%) patients in the tenecteplase group had died as compared with 2 (11.76%) in the streptokinase group and 3 (12.5%) in the heparin group. The difference between treatment group was nonsignificant (p>0.05).
Secondary efficacy parameters
Data on improvement in the secondary parameters is presented in Table 2. After treatment, all the three treatment group have shown significant improvement in the rate of dyspnoea at all evaluations compared with baseline data (p<0.05). Greater percentage of patients receiving tenecteplase showed improvement compared with those receiving streptokinase and heparin. However, the difference between the treatment group was not significant (p>0.05).
RBBB was observed in more number of patients in tenecteplase and streptokinase group compared with heparin. By day 7, there was 100% resolution of RBBB only in the tenecteplase group. In the streptokinase group, 2 of the 6 patients observed at baseline continued to have RBBB at day 7, whereas there was no resolution in RBBB observed in 1 patient who was treated with heparin.
Significant reduction in heart rate was seen post treatment in all three treatment group (p<0.05). The reduction in heart rate from baseline was more in tenecteplase treated patient compared with streptokinase and heparin treated patients. The difference in heart rate reduction in tenecteplase group compared with streptokinase and heparin was statistically significant (p<0.05).
Systolic blood pressure increased significantly from baseline only in the tenecteplase treated patients and no significant change was seen in the streptokinase and heparin group. Also, there was no significant change from baseline in the diastolic blood pressure in any of the treatment group.
Increase in the oxygen saturation was significant (p<0.05) and markedly higher in the tenecteplase treated patients compared with the streptokinase and heparin treated patients.


Safety Evaluation

Bleeding complications were noted at day 7 after the treatment. The incidence of overall bleeding in the three groups was comparable [tenecteplase: 2 (3.2%), streptokinase: 1 (5.88%), heparin: 1 (4.17%)]. No intracranial bleeding or fatal bleeding episode was found in either group.


Table 1

Another alt text

Table 1
Baseline Characteristics of the patients.

Table 2

Another alt text

Table 2
Improvement in secondary efficacy parameters.

Discussion

The clinical course and prognosis of PE patients vary widely and is life threatening. For example in patients with massive PE, 50%, 70% and 85% of patients die within 30 minutes, 1 and 6 hours of the onset of symptoms, respectively [13]. Despite initiating treatment with anticoagulation, 8% to 17% of patients experience failure or recurrence after 3 to 6 months [14-16]. On the other hand thrombolytic therapy directly dissolves the thrombi and more rapidly reverses hemody­namic instability compared with anticoagulant therapy. The current guidelines recommend the use of thrombolytics only in high risk patients with massive PE associated with circulatory collapse [1]. Questions related to its utility in lesser severe patients remain subject of investigation as clinical practice seems to be far different from the recommended guidelines. Tenecteplase is an alteplase molecule with several advantages as discussed earlier and offer great therapeutic convenience in thrombolysis as against the older thrombolytics. Apart from application in treatment of massive PE, its use has also been documented in submassive and hemodynamically stable patients of PE with right ventricular dysfunction [17,18]. There are fewer studies on tenecteplase use in pulmonary embolism till date.
All patients irrespective of their clinical status of PE (minor, submassive, massive) were treated either with tenecteplase, streptokinase or heparin. This was contrary to the recommendations for the use of thrombolytics in only hemodynamically compromised patients. However, studies have been reported with use of tenecteplase in hemodynamically stable patients as well with favourable results [17,19]. The major risk factors for PE in the present study were history of DVT, hospitalization and diabetes.
In the present study, death occurred in 4.84%, 5.88% and 8.33% and 9.67%, 11.76% and 12.5% patients in the tenecteplase, streptokinase and heparin group by day 7 and 180, respectively. Though the difference between treatment group was nonsignificant (p>0.05), tenecteplase was found to produce numerically better results than the other two. The result could have been different if the treatment group would have been balanced with respect to the number of patients. Since this was a retrospective study, we did not have control on the number of patients in each group. More number of patients was assigned to tenecteplase compared with that of streptokinase and heparin, which is also suggestive of the preference of physician for tenecteplase. Thrombolytic therapy is known to significantly reduced mortality in submassive PE compared with heparin anticoagulation alone [20]. In addition all patients subsequent to treatment showed significant improvement in clinical symptom of PE i.e. dyspnoea, heart rate and oxygen saturation. The difference between the group was not significant but greater percentage of patients in the tenecteplase group shown improvement when compared with streptokinase and heparin.
Treatment with thrombolytic is known to carry a risk of major bleeding, including intracranial hemorrhage. Clinically relevant nonmajor bleeding was observed in 3.2% of patients in the tenecteplase group, 5.88% in the streptokinase group and 4.17% of patients in heparin group. No intracranial bleeding or fatal bleeding episode was observed in any treatment group. Literature reports a wide range of incidence for major bleeding (0 to 33%) and intracranial hemorrhage (0 to 7.4%); the wide range is because of the small sample sizes of many of these studies [21,22]. In a meta-analysis that included 16 studies (n=2115), incidence of major and intracranial bleeding was 9.24% and 1.46%, respectively and was also significantly more compared with anticoagulant therapy [23].
The present study demonstrated that thrombolytic and anticoagulant therapies both are safe. However, therapy can be tailored as per the clinical status of the patient. Anticoagulants can always be the drug of choice in mild conditions, whereas consideration should be given to the use of thrombolytic in moderate to critically ill patients. There are some limitations with our study and should be taken into consideration. Being a retrospective study we did not had control on treatment assignment and nor on the number of patients in each treatment group. There were unequal number of patients in each treatment group and this might have some impact on the results of the study. Considering lack of studies in patients with PE, this data can be useful in planning larger trials that can influence treatment and management of these patients.


Acknowledgment

The authors would like to thank the staff at KIMS Hosptial for helping in conduct of this study.


References

  1. Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033-69.
  2. Pelliccia F, Schiariti M, Terzano C, Keylani AM, D'Agostino DC, Speziale G, et al. Treatment of Acute Pulmonary Embolism: Update on Newer Pharmacologic and Interventional Strategies. BioMed Research International. Biomed Res Int. 2014:410341.
  3. Ohteki H, Norita H, Sakai M, Narita Y. Emergency pulmonary embolectomy with percutaneous cardiopulmonary bypass. Ann Thorac Surg. 1997;63(6):1584-6.
  4. Widimský J, Malý J, Eliáš P. Doporucení pro diagnostiku a lécbuakutníplicníembolie. Vnitr. Lék.2008;54:1S25-1S72.
  5. Belohlávek J, Dytrych V, Linhart A. Pulmonary embolism, part I: Epidemiology, risk factors and risk stratification, pathophysiology, clinical presentation, diagnosis and nonthrombotic pulmonary embolism. Experimental & Clinical Cardiology. 2013;18(2):129-138.
  6. Douma RA, Kamphuisen PW, Büller HR. Acute pulmonary embolism. Part 1: epidemiology and diagnosis. Nat Rev Cardiol. 2010;7(10):585-96.
  7. Lucena J, Rico A, Vázquez R, Marín R, Martínez C, Salguero M. et al. Pulmonary embolism and sudden-unexpected death: prospective study on 2477 forensic autopsies performed at the Institute of Legal Medicine in Seville. J Forensic Leg Med. 2009;16(4):196-201.
  8. Ullmann M, Hemmer W, Hannekum A. The urgent pulmonary embolectomy: mechanical resuscitation in the operating theatre determines the outcome. Thorac Cardiovasc Surg. 1999;47(1):5-8.
  9. Agnelli G. Anticoagulation in the prevention and treatment of pulmonary embolism. Chest. 1995;107(1 Suppl):39S-44S.
  10. Arcasoy SM, Kreit JW. Thrombolytic therapy of pulmonary embolism: a comprehensive review of current evidence. Chest. 1999;115(6):1695-707.
  11. Tanswell P, Modi N, Combs D, Danays T. Pharmacokinetics and pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial infarction. Clin Pharmacokinet. 2002;41(15):1229-45.
  12. Melandri G, Vagnarelli F, Calabrese D, Semprini F, Nanni S, Branzi A. Review of tenecteplase (TNKase) in the treatment of acute myocardial infarction. Vascular Health and Risk Management. 2009;5:249-256.
  13. Stulz P, Schläpfer R, Feer R, Habicht J, Grädel E. Decision making in the surgical treatment of massive pulmonary embolism. Eur J Cardiothorac Surg. 1994;8(4):188-93.
  14. O'Sullivan EF. Duration of anticoagulant therapy in venous thrombo--embolism. Med J Aust. 1972;2(20):1104-7.
  15. Holmgren K, Andersson G, Fagrell B, Johnsson H, Ljungberg B, Nilsson E, et al. One-month versus six-month therapy with oral anticoagulants after symptomatic deep vein thrombosis. Acta Med Scand. 1985;218(3):279-84.
  16. [No authors listed]. Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism. Research Committee of the British Thoracic Society. Lancet. 1992;340(8824):873-6.
  17. Becattini C, Agnelli G, Salvi A, Grifoni S, Pancaldi LG, Enea I, et al. Bolus tenecteplase for right ventricle dysfunction in hemodynamically stable patients with pulmonary embolism. Thromb Res., 2010, 125:e82-e86.
  18. Bhuvaneswaran JS, Premchand RK, Iyengar SS, Rajeev Khare, Chabra CB, Padmanabhan TN, et al. Tenecteplase in the treatment of acute pulmonary thrombo-embolism. J Thromb Thrombolysis. 2011;31(4):445-8.
  19. Büller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE, et al. Antithrombotic therapy for venous thromboembolic disease: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126(3):401S-408S.
  20. Konstantinides S, Geibel A, Heusel G. Management Strategies and Prognosis of Pulmonary Embolism 3 Trial Investigators: Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002;347:1143 1150.
  21. Levine M, Hirsh J, Weitz J. A randomized trial of a single bolus dosage regimen of recombinant tissue plasminogen activator in patients with acute pulmonary embolism. Chest. 1990;98:1473-1479.
  22. Goldhaber S, Agnelli G. Levine M. Reduced dose bolus alteplase vs conventional alteplase infusion for pulmonary embolism thrombolysis: an international multicenter randomized trial. Chest. 1994;106:718-724.
  23. Chatterjee S, Chakraborty A, Weinberg I, Kadakia M, Wilensky RL, Sardar P, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014;311(23):2414-21.