J Thromb Thrombolysis (2014) 38:24–29

DOI 10.1007/s11239-013-0985-x

Efficacy and safety of tenecteplase in pulmonary embolism

Anand N. Shukla • Bhavesh Thakkar •
Ashwal A. Jayaram • Tarun H. Madan •

Gaurav D. Gandhi

Published online: 23 August 2013

Ó Springer Science+Business Media New York 2013

Abstract Pulmonary embolism (PE) is a relatively severe hypoxemia. There was significant reduction in right
common life-threatening cardiovascular condition associ- ventricular systolic pressure and improvement in right
ated with significant morbidity and mortality. We present ventricular dysfunction. Our study shows that tenecteplase
the efficacy and safety data of weight-adjusted tenecteplase is very effective and safe in the treatment of PE with
in 30 consecutive patients of acute PE. 30 patients (22 minimal risk of bleeding in high risk group and interme-
male, 8 female) with acute PE were included in the study diate risk and even in selective low risk category group of
and divided into three groups: (1) Acute PE complicated by patients. However, in view of small number of patients in
shock stage and/or persistent hypotension (12 patients). (2) study group, a large multicentre randomized study would
RV dilatation and/or dysfunction without hypotension (14 be required to draw a firm conclusion regarding the
patients). (3) Severe hypoxemia without hypotension and thrombolysis in low risk category patient.
RV dysfunction (4 patients). Predominant symptoms were
dyspnoea, cough, chest pain, syncope and haemoptysis, Keywords Pulmonary embolism (PE)
Right
noted in 100 % (30), 40 % (12), 54 % (16), 32 % (9) and bundle branch (RBBB)
Right ventricular
10 % (3) of patients respectively. RV dilatation and dys- hypertrophy (RVH)
Supra ventricular tachycardia
kinesia were present in 86 %, septal paradoxical movement (SVT)
in 73 % and inferior venacava collapse absent in 53 % of
patients respectively. 12 patients presented with acute PE
and cardiogenic shock, 14 patients showed RV dilatation Introduction
and dysfunction with systolic BP [90 mmHg and four
patients were having RV dilation without dysfunction but Pulmonary embolism (PE) is a life-threatening condition
associated with significant morbidity and mortality. In
massive PE and consequent right ventricular failure, resto-
A. N. Shukla (&)
B. Thakkar
A. A. Jayaram
ration of pulmonary arterial flow is urgently required.
T. H. Madan
G. D. Gandhi Although anticoagulation is the standard treatment of PE,
U.N. Mehta Institute of Cardiology and Research Centre
thrombolytic therapy, with its ability to produce rapid clot
(UNMICRC), Civil Hospital Campus, Ahmedabad 380016,
Gujarat, India lysis, has long been considered to be an alternative [1].
e-mail: dranand1978@[Link] Thrombolytic therapy has shown to improve survival,
B. Thakkar especially in patients with high risk PE [2]. Despite the
e-mail: bthakkarin@[Link] approval of streptokinase, urokinase and alteplase for
A. A. Jayaram thrombolysis in PE, the efficacy of these thrombolytic
e-mail: [Link]@[Link] remains unclear due to the high mortality associated with this
T. H. Madan condition and lack of large randomized controlled trials [3,
e-mail: drtarunmadan@[Link] 4]. Tenecteplase is a genetically engineered product of the
G. D. Gandhi Alteplase molecule. Mutations of alteplase at three locations
e-mail: drgg_29@[Link] result in a more fibrin specific thrombolytic agent with a

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Efficacy and safety of tenecteplase in pulmonary embolism 25

longer half life. Such properties allow bolus administration, for 2 days keeping APTT 50–70 s. Data were collected at
leading to faster reperfusion of occluded arteries. Tenec- the entry into the study. Symptoms and signs on admission,
teplase is equivalent to front loaded alteplase in terms of medications, arterial blood gas analysis, biochemical
mortality and is the only bolus thrombolytic agent for which marker and results of chest X-ray, ECG, echocardiography
equivalence has been demonstrated [5]. We aimed to deter- and lower limb doppler were recorded. All patients were
mine the efficacy and safety of weight-adjusted tenecteplase subjected for multidetector CT pulmonary angiography.
in 30 patients of acute PE. Patients were divided into three categories.
(1) Acute PE with cardiogenic shock (massive PE-12
patients)
Materials and methods
(2) Acute PE with blood pressure [90 mmHg but shows
RV dilatation and dysfunction (14 patients, submas-
Thirty patients (22 male and 8 female patients) with acute
sive PE).
PE treated in a tertiary referral care centre, Ahmedabad
(3) Hypoxemia (SaO2 \94 % with room saturation) and
from July 2010 to July 2012 were included in the study.
RV dilatation without RV dysfunction and stable
Patients with age 18 years or older with acute PE con-
hemodynamic condition (4 patients) [7, 8]
firmed by multi detector CT pulmonary angiography were
included in the study. Patients who had chronic pulmonary Pulmonary hypertension was defined as mean pulmon-
hypertension, severe COPD, contraindication to thrombo- ary artery pressure of more than 30 mmHg [8]. IHD was
lytic therapy, a known significant bleeding risk/bleeding defined as the history of MI or CAD [8]. Left sided heart
within the last 6 months, thrombolysed within the previous failure was defined as the presence of S3 gallop, h/o CCF
4 days or heparinised for more than 72 h were excluded or pulmonary oedema on chest X-ray [8]. COPD or ILD
from the study. Patients with vena cava filter insertion or were defined by chest X-ray [8]. Follow up of the patients
pulmonary thrombectomy within the previous 4 days or was done on a daily basis during the course of the hospi-
with an uncontrolled hypertension defined as systolic talization during which symptoms and signs of recurrent
BP [180 mmHg and/or diastolic BP [110 mmHg at venous thromboembolism or bleeding were sought. For all
admission were also excluded. Patients with treatment with patients, ultrasonography of the lower limbs was strongly
an investigational drug under another study and with encouraged at enrolment. Patients with suspected new or
known hypersensitivity to any of the thrombolytic agents recurrent deep-vein thrombosis on the basis of the clinical
or unfractionated heparin were also excluded. Patients with findings underwent ultrasonography, whichever test had
pregnancy, lactation or parturition within the previous been previously performed and had results available for
30 days were excluded. However, women of childbearing comparison. The criterion for deep-vein thrombosis was
age who had a negative pregnancy test or used a medically either a constant intraluminal filling defect on venography
accepted method of birth control before were included into or a lack of compressibility on ultrasonography. [8].
the study. Patients with known coagulation disorder Complete blood counts, platelet count and coagulative
(including ongoing treatment with vitamin K antagonists) parameters were monitored during the initial treatment per-
were also excluded from the study. Fisher’s exact test and iod and platelet counts and coagulative parameters were
unpaired t test were used for the statistical purposes. obtained if there were any signs of bleeding. Bleeding was
Informed consent of all the patients was taken prior defined as major if it was overt and associated either with a
enrolment into the study. The study design was approved decrease in the haemoglobin concentration by at least 2.0 g/
by the Ethical committee of the institute. dl or need for transfusion of two or more units of blood, or if
the bleeding was intracranial or retroperitoneal [9]. Deaths
Initial treatment were classified as due to PE (when there was strong clinical
evidence or evidence at autopsy), haemorrhage, cancer, or
Tenecteplase is approved for thrombolysis in ST-segment other causes (including unknown causes) [9]. Patients were
elevation myocardial infarction (STEMI) by USFDA in diagnosed to have recurrent PE if there was a new intralu-
2000 and by the Drug Controller General of India in 2007. minal filling defect or a new sudden cut-off in an arterial
All the patients received in-hospital weight-adjusted dos- branch that was not present on the first angiogram [9].
age of tenecteplase as prescribed by the manufacturer in
addition to standard heparin and oral anticoagulant therapy. Echocardiography assessment
[6] Tenecteplase was given as an intravenous weight
adjusted bolus (given over 5 s) at a dose ranging from 30 to The base line echocardiographic assessment for any
50 mg (0.5 mg/kg), with a 5 mg step-up for every 10 kg thrombus in the inferior venacava (IVC), right atrium
increase from 60 to 90 kg. Heparin infusion was continued or right ventricle; right ventricular function/dilatation,

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26 A. N. Shukla et al.

tricuspid regurgitation and any evidence of thrombus in the twelve patients four patients had received thrombolytic
pulmonary arteries was carried out within 24 h of admis- therapy before MDCT was performed due to high suspi-
sion. Echocardiography was repeated after 24 h, at seven cious of PE and hemodynamic instability. All four patients
days and just before discharge. Echocardiography was improved. There was alleviation of dyspnoea, chest pain
repeated at every follow-up. Right ventricular dilation and haemoptysis in all patients. Improvement in sinus
(RVD) was defined as the right/left ventricle end-diastolic tachycardia and increase in the oxygen saturation (SaO2)
dimension ratio [1 in the apical 4-chamber view and/or was seen at the time of discharge as compared to the time
[0.7 in parasternal long axis in the absence of right ven- of presentation. Pre-discharge echocardiographic evalua-
tricle hypertrophy [10]. tion revealed significant reduction in right ventricular
systolic pressure and improvement in right ventricular
dysfunction in all the patients and regression of RVH in
Results two patients. The outcomes of tenecteplase therapy in
survived patients are depicted in Tables 1, 2.
The 30 cases included 22 males and 8 females with a mean However, the resolution of PE on follow up CT pulmon-
age of 46 ± 12.85 years. 50 % of the patients were obese (n- ary angiography was documented in only 26 patients. There
16) and 40 % were overweight (n-12).Mean weight was was no major/minor bleeding events during the study. No
78 ± 12.33 kg. The predominant presenting symptoms other adverse events were reported during this study. At the
were dyspnoea (30 pt), cough (12 pt), chest pain (16 pt), first follow up visit after one month of tenecteplase therapy,
syncope (9 pt) and haemoptysis (3 pt), which were noted in all patients were clinically stable. Unfortunately three
100, 53, 46, 33 and 6 % of patients respectively. Of the 30 patients died after 90 days; one of the patient died due to
patients, 12 patients had hypotension (defined as systolic underlying adenocarcinoma of lung, second patient died of
blood pressure\90 mmHg) which recovered in all patients. recurrent large PE also known case of malignancy and third
Predisposing factors such as deep vein thrombosis (24 pt)
and cancer (2 pt) were found in 73 and 6 % of the patients.
Table 1 Characteristics of the patients on the time of admission and
H/o travelling was present in one patient. Vitamin B12 levels pre-discharge
were done in all patients among which, 14 patients had levels
Parameter On admission Pre-discharge p-value
in the lower range (226.7 ± 52.24 pg/dl). Homocysteine
levels were done in all patients and 16 patients had signifi- No. of patients 30 30 -
cantly high levels (31.67 ± 21.52 lg/dl). Presenting symptoms
The ECG findings included sinus tachycardia (100 %), T Dyspnoea 30/30 (100 %) 0 \0.0001*
inversions in V1–3 (100 %), low voltage complexes (60 %), Chest pain 16/30 (52 %) 0 \0.0001*
ST depressions in lead 2, 3 and V4–6 (73 %), S1Q3T3 Haemoptysis 3/30 (10 %) 0 0.4915**
(46 %), RBBB (13.3 %), RVH (13.3 %), and SVT (6 %). Syncope 09/30 (30 %) 0 0.001*
Most of the ECG changes resolved with the resolution of RV failure 6/30 (20 %) 0 0.023*
thrombus. Sinus tachycardia and right bundle branch block Clinical signs
(RBBB) resolved in all patients. Right ventricular hyper- Heart rate 108.8 ± 10.58 88.13 ± 14.54 \0.0001#
trophy (RVH) regressed in 6.6 % (2 pt) of the patients. The Investigations
baseline echocardiography findings included RV dilatation
Pa O2 (mmHg) 97.29 ± 32.92 166.3 ± 34.84 \0.0001#
in all patients, RV dilatation and dysfunction (80 %) septal
PCO2 (mmHg) 25.75 ± 5.476 33.57 ± 3.33 \0.0001#
paradoxical movement in 73 % and IVC collapse absent in
SpAO2 (9 %) 91.05 ± 4.99 96.92 ± 2.14 \0.0001#
53 % of patients respectively. There was no evidence of
RVSP (mmHg) 78.67 ± 14.92 42.27 ± 5.04 \0.0001#
thrombus in IVC, right atrium or right ventricle. Moderate to
RV dysfunction 26 (86 %) 0 \0.0001#
severe tricuspid regurgitation was observed in 22 (63 %)
ECG changes
patients. RVH was seen in 4 (13.3 %) patients. The diagnosis
Sinus tachycardia 30 (100 %) 0 \0.0001*
of PE was confirmed in all patients using multidetector CT
RBBB 4/30 (13.3 %) 0 0.1124**
pulmonary angiography. In 40 % (12 pt) of the patients, there
RVH 4/30 (13.3 %) 2/30 (6.6 %) 0.6707**
was evidence of thrombosis in the right and/or left pul-
monary artery. In another 20 % (6 pt) there was evidence of Pa O2 partial pressure of oxygen, PCO2 partial pressure of carbon
thrombus involving segmental and subsegmental pulmonary dioxide, SpAO2 percentage saturation of oxygen in the arterial blood,
RVSP right ventricular systolic pressure, RV right ventricle, ECG
arteries. In 40 % (12 pt) of the patients has evidence of electrocardiogram, RBBB right bundle branch block, RVH right
thrombus main pulmonary artery. ventricular hypertrophy
Of 30 patients who received weight-adjusted tenectep- * p value significant using Fisher exact test. # p value significant
lase injection, all patients survived. In group one, out of using unpaired t test. ** p value nonsignificant using Fisher exact test

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Efficacy and safety of tenecteplase in pulmonary embolism 27

Table 2 Symptomatology, clinical signs and ECG at time of presentation, ECHO and MDCT pulmonary angiography in group 1, group 2 and
group 3 category patients
Group:1 (n-12) Group:2 (n-14) Group:3 (n-4)
Number of pt
M (9) F (3) M (11) F (3) M (2) F (2)

Symptoms (No. of pt/ % of pt)

Dyspnoea (30/100 %) 9 3 11 3 2 2
Chest pain (16/52 %) 9 2 4 1 0 0
Syncope (9/30 %) 3 1 2 1 1 1
Hemoptysis (3/10 %) 0 0 2 0 1 0
Cough (12/40 %) 3 2 4 2 1 0
Sign and ECG (No. of pt/ % of pt)
Tachycardia (26/86 %) 9 3 10 2 1 1
Tachypnoea (28/93 %) 9 3 11 3 1 1
RBBB (4/13 %) 2 1 1 0 0 0
S1Q3T3 (9/30 %) 3 1 3 1 1 0
ST depression V1–V3 and inferior lead (24/80 %) 9 3 10 2 0 0
T inversion V1–3(30/100 %) 9 3 11 3 2 2
Low voltage (20/66 %) 9 2 8 1 0 0
RVH (4/13 %) 2 1 1 0 0 0
Aetiology (No. of pt/ % of pt)
DVT (24/80 %) 7 2 9 3 2 1
Obesity (17/56 %) 4 2 7 2 1 1
H/o travel (2/6 %) 0 0 1 0 1 0
Cancer (2/6 %) 2 0 0 0 0 0
Echo findings (No. of pt/ % of pt)
RV dilatation and dysfunction (26/86 %) 9 3 11 3 0 0
RV dilatation (30/100 %) 9 3 11 3 2 2
IVS paradoxical (22/73 %) 9 2 9 2 0 0
IVC collapse absent (16/53 %) 8 3 4 1 0 0
Mod-sev TR (22/73 %) 9 3 7 2 1 0
MDCT pulmonary angiography (MDCT pul (n/ %))
MPA throm (12/40 %) 9 2 1 0 0 0
LPA and/or RPA throm (12/40 %) 9 2 1 0 0 0
Segmental and subsegmental (6/20 %) 0 0 1 1 2 2
M male, F female, n number of patient, % % of total study population, pt patient, RBBB right bundle branch block, S1Q3T3 S wave in lead I, Q
wave in lead III, T inversion lead III, RVH right ventricle hypertrophy, DVT deep vein thrombosis, H/o history of, RV right ventricle, IVS
interventricular septum, IVC inferior venacava, mod-sev TR-moderate to severe tricuspid regurgitation MDCT pul multidetector CT pulmonary
angiography, MPA main pulmonary artery, RPA right pulmonary artery, LPA left pulmonary artery, Throm thrombus
Group 1: Patients with hemodynamic unstability. Systolic BP \90 mmHg, RV dilatation and dysfunction
Group 2: RV dilatation and dysfunction but Systemic BP [90 mmHg
Group 3: Without RV dysfunction and hemodynamic stable

patient died due to oral anticoagulation related major intra- USFDA approval of streptokinase for acute PE in 1977.
cerebral hemorrhage. The ICOPER registry [11] reported a 2-week-mortality of
15.9 % in patients with RVD in comparison to 8 % in
patients without RVD. In MAPPET registry [12], 10 % of
Discussion the patients with RVD died within 30 days as compared to
4.1 % without RVD. Thrombolytic agents (e.g. urokinase,
The use of thrombolytics for the treatment of PE has streptokinase and alteplase) rapidly dissolve the thrombo-
remained controversial over several decades since the embolic obstruction and have favourable effects. The

123
28 A. N. Shukla et al.

greatest benefit was observed when treatment was initiated study by Tayama et al. [16] demonstrated RV dyskinesia in
within the first 48 h. However, thrombolysis can be helpful 80 % of the patients, septal paradox in 46.7 % and RVD in
for patients who had symptoms for up to 14 days [13]. 68 % of the patients which were very similar to our study.
The data of 30 patients in this study depicts favourable They also showed that in 71.4 % of the patients, ECG dem-
efficacy of tenecteplase in the management of acute PE in onstrated more than 2 findings including S1, Q3 and T wave
terms of hemodynamic improvement and right ventricular inversions in V1–3. Various studies have also shown S1Q3T3
systolic pressure reduction. Of the 30 patients who were pattern in 68.29 % of the patients, RBBB in 26.8 % and ST–T
included in the study, there was resolution of the thrombus in changes in 26.83 % of the patients [3]. Tayama et al. [16] also
all but four patients who had massive PE with evidence of showed that the significant predictors for mortality were sys-
thrombus in the main including segmental pulmonary tolic blood pressure \100 mmHg, requirement of dopamine
arteries. It was observed that the resolution of symptoms and infusion rate of [5 lg/kg/min, pH \7.4, PaCO2 [40 torr,
thrombus on follow up CT scan was earlier in patients who base excess \5 mmol/L, urine output \0.8 ml/kg/h, intuba-
presented within 48 h of symptoms onset. Symptoms like tion, cardiopulmonary resuscitation, duration from attack to
dyspnoea, chest pain, and syncope improved in all patients. emergency room [5 h, shock duration [4 h, aspartate ami-
All of the 12 patients who had evidence of RV failure clin- notransferase[100 U/L, alanine aminotransferase[100U/L
ically improved after thrombolysis with tenecteplase. In all and lactate dehydrogenase[600 U/L.
patient with RV dilatation on echocardiographically, chan- As our study did not have any immediate deaths and all
ges reverted back to normal after thrombolysis. The present the three late deaths were attributable to recurrent PE, we
study did not find any incidence of major/minor bleeding could not demonstrate any such associations. Of 30
adverse effects with tenecteplase during index hospitalisa- patients, three patients died after 90 days of follow up in
tion. Functional capacity of the patients also improved as view of recurrent PE. All these patients had presented later
assessed by 6 min walk test at time of discharge. than 14 days, were thrombolysed later, had evidence of
Tenecteplase is a bioengineered tissue plasminogen acti- thrombus in the main PA and had underlying hypercoag-
vator produced by recombinant DNA technology using ulable states. Among these three patients, two patients had
established mammalian cell line (Chinese hamster ovary persistent RV dysfunction and one patient died of under-
cells). A large European multicentre, double blind, PE lying adenocarcinoma of lung. There was also partial res-
thrombolysis study (PEITHO) [14] is underway. This study olution of thrombus in the follow up CT pulmonary
will randomize patients with normotensive PE, RV enlarge- angiography among these patients. Earlier studies have
ment on echocardiography (RV/LV[0.9) and elevated levels shown cancer, left sided congestive heart failure; chronic
of cardiac troponin to receive either a bolus regimen of TNK lung diseases and age more than 60 years are significantly
and heparin or TNK alone. A randomized, double blind pla- associated with one year mortality [8]. In one of the earliest
cebo controlled study done to assess the effect of TNK on RV reports, patients with PE had a 17 % mortality rate, but PE
dysfunction showed that single bolus dose of TNK was was itself a cause of death in only 3 % of the patients [17].
associated with significant reduction of RV:LV end diastolic In patients without pre-existing cardiac or pulmonary dis-
diameter ratios [10]. Tenecteplase has three properties that ease, the reported mortality rate is low ranging from 3 to
favour its use to treat PE [15]. First advantage is of it being a 9 % [18, 19]. Among the patients with massive PE, Hall
single bolus dose thrombolytic. Second, its bolus dosing may et al. described an 18 % in-hospital mortality rate and a
allow more rapid formation of plasmin, possibly allowing 5-year mortality rate of 17 % who survive to discharge
more rapid clearance of clot and quicker resolution of symp- [20]. May be as a result of earlier diagnosis and adminis-
toms in comparison to infusion regimen. Thirdly, there is no tration of effective thrombolytic agent like tenecteplase in
requirement of continuous infusion of thrombolytic therapy. our study all the patients survived the index event.
All patients have received intravenous heparin infusion as per Thus, single bolus administration of tenecteplase in
APTT. In a study of 41 cases of PE by Bhuvaneswaran et al. comparison to currently approved thrombolytic agents like
[3], presenting symptoms of dyspnoea, chest pain, syncope streptokinase, urokinase and rtPA, allows drug adminis-
and haemoptysis were found in 40 (97.56 %), 19 (46.34 %), 9 tration in hemodynamically unstable patients with high
(21.95 %) and 6 (14.63 %) patients respectively which was suspicion of PE with favourable outcomes.
very similar to our study. Of 41 patients in this study, 18 had
hypotension which recovered in all patients till the time of
discharge (p \ 0.0001). Bhuvaneswaran et al. [3] also showed Conclusion
resolution of RBBB and RVH as documented on echocardi-
ography along with a significant reduction in right ventricular Our study shows that even though tecneteplase is not
systolic pressure in 18 patients who underwent 2-D echocar- currently approved by for the treatment of acute PE in the
diography both before and after the tenecteplase therapy. The current guidelines [21, 22] it is very effective and safe in

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Efficacy and safety of tenecteplase in pulmonary embolism 29

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