30 Journal of The Association of Physicians of India Vol.

63 April 2015

Original Article

Post-Reteplase Evaluation of Clinical Safety &

Efficacy in Indian Patients (Precise-In Study)
RK Singh1, A Trailokya2, MM Naik3

Abstract
Background: ST elevated myocardial infarction is a serious and life-threatening condition. In patients suitable
for thrombolytic treatment, time is critical and reperfusion should be initiated as soon as possible. Reteplase is
commonly used in the management of ST elevated myocardial infarction.
Objective: To assess the safety and efficacy of intravenous Retelex (Reteplase) injection in management of patients
with ST elevated myocardial infarction in clinical practice.
Material and methods: An open label, non-comparative, multicentric, post-marketing observational study was
conducted in >18 years of patients with ST elevated myocardial infarction (STEMI) receiving Retelex. All patients
received 20 units Retelex within 6 hours after the onset of acute myocardial infarction (AMI) symptoms. The dose
was given as two 10 unit Intravenous injections each over two minutes 30 minutes apart. Evaluation criteria: Patients
were followed on day 1, 3, 5/7 and 30. The primary evaluation criteria was total number of patients showing
clinically successful thrombolysis based on 50% resolution of ST-elevation in the maximum affected (adjacent)
leads within 90-120 minutes of initiation of Reteplase and resolution of chest pain. Secondary evaluation criteria
included percentage of patient requiring rescue percutaneous coronary intervention (PCI), percentage of patient
underwent angioplasty or CABG after thrombolysis. Door to needle time was also recorded in patients receiving
the study drug. Global assessment of efficacy and safety was done by patient as well as investigator. All adverse
events were recorded for safety assessment. Statistical analysis: Mean and percentage were calculated for primary
efficacy parameters i.e. 50% resolution of ST elevation and resolution of chest pain. Chi square test was used for
comparing the difference between diabetes versus non-diabetes patients for primary efficacy variables as well
as for comparing the number of patients requiring rescue PCI, angioplasty and CABG between these two groups.
Results: A total of 228 patients were enrolled out of which 140 were having diabetes mellitus. Out of all patients,
68.9% had ST elevated anterior wall myocardial infarction. Resolution of 50% of ST elevation and resolution of
chest pain was reported in 90.50% and 95.4% patients respectively. No significant difference was seen in primary
efficacy variables between diabetes versus non-diabetes patients (p=0.1538 for 50% ST elevation resolution,
p=0.4031 resolution of chest pain). Rescue PCI was required by 7.6% patients while angioplasty and CABG was
done in 22% and 16.8% patients, respectively. No significant difference was seen in diabetes versus non-diabetes
patients requiring rescue PCI (p=0.1059), angioplasty (p=0.2172) and CABG (p=0.9128). The incidence of adverse
event in this study was 5.3%.
Conclusion: Reteplase IV Injection-recombinant plasminogen activator is effective and well tolerated in the
management of ST elevated myocardial infarction (STEMI) in Indian patients including diabetes patients.

Editorial Viewpoint
Early thrombolysis should be made available to all the patients across India to be administered while
transporting patients in ambulance.
This is an open label, non-comparative post-marketing surveillance.
There is a definite improvement in therapeutic armamentarium for thrombolysis by addition of Reteplase.

1
Consultant Cardiologist, Department of cardiology, Bhopal Memorial Hospital and Research Center (BMHRC), Bhopal, Madhya Pradesh; 2Chief Medical Advisor, 3Chief Manager,
Medical Services Division, Abbott Healthcare Private Limited, Mumbai, Maharashtra
Received: 03.07.2014; Revised: 08.10.2014; Accepted: 04.11.2014
 32 Journal of The Association of Physicians of India Vol. 63 April 2015
Introduction
N on-communicable diseases
are rapidly increasing and
mortality due to non-communicable
diseases is increasing at a rapid
pace. Cardiovascular disease, one
of common non-communicable
diseases is responsible for high
morbidity and mortality all over
the world. 1 There are about 30
million patients with CHD in
India. Coronary heart disease is
more prevalent in Indian urban
populations. Epidemiological
studies have demonstrated the
prevalence of CHD in rural adult
is less (3-5%) compared to urban
(7-10%) adults.2 According to
estimates a total of nearly 64
million cases of CVD are likely in
the year 2015. 3 One of the serious
complications of the CAD is ST-
elevation myocardial infarction
(STEMI), which is a life-threatening
c l i n i c a l e m e r g e n c y . 4 Pa t i e n t s
with acute coronary syndromes
i n In di a h a ve a h i g h e r r a t e of
STEMI compared to developed
countries.5 ST elevation myocardial
infarction (STEMI) can be treated
by primary percutaneous coronary
intervention (PPCI) and fibrinolysis.
Percutaneous coronary intervention
if done in timely manner is superior
to fibrinolysis. 6 However, this may
not be possible in many settings
because of challenges like time lag
in transferring the patient, lack of
catheterization facility and limited
number of skilled practitioners. In
patients suitable for thrombolytic
treatment, time is critical and
reperfusion should be initiated
as soon as possible.4 Despite
availability of good treatment,
mortality from acute myocardial
infarction (AMI) is showing no
further reduction due to the pre-
hospital phase and in-hospital
delays. 5 Hence for management of
STEMI, immediate administration
of a fibrinolytic followed by
angiogram and percutaneous
intervention (PCI) between 3-24
hours after fibrinolytic therapy may
be an attractive option. 7 Reteplase
is a plasminogen activator which
mimics endogenous tissue
p l a s m i n o g e n a c t i va t o r ( t - PA) ,
a serine protease, converting
plasminogen to plasmin and
thereby precipitating thrombolysis.
It is a third-generation recombinant
form of fibrin specific t-PA. 8 The
half-life of reteplase is longer than
that of alteplase; hence it can be
used as bolus injection. 9 The ease
of administration of reteplase
because of simple dosage regimen
helps for prehospital initiation
of thrombolytic treatment in
patients with ST-segment elevation
myocardial infarction (STEMI).
The advantage with this regime is
reduction in the time to treatment
which is an important factor in
improving long-term survival. 8
Objective
The objective of the study was
to evaluate safety and efficacy of
intravenous Retelex (Reteplase)
injection in management of patients
w i t h S T e l e va t e d m y o c a r d i a l
infarction in clinical practice
Material and Methods
An open label, non-comparative,
multicentric, post-marketing
observational study was conducted
in adult patients (>18 years of
age) with ST elevated myocardial
infarction (STEMI) who received
Retelex. The decision to administer
Retelex (Reteplase) along with other
adjuvant drugs was taken solely by
the treating physicians as a part
of their clinical management. The
patients having contraindication
to the use of thrombolytic, patients
with internal active bleeding or
known history of hemorrhagic
diathesis or history of previous
cardiovascular accident (CVA),
transient ischemic attack (TIA)
of any kind, intracranial tumor,
arteriovenous malformation,
cerebral aneurysm, major surgery,
parenchymal biopsy, ocular surgery
and/or severe traumatism within 6
weeks prior to screening for study
were excluded from the study.
The patients with unexplained
puncture in a non-compressible
vascular location in the last 24
hours prior to screening for study
and those with confirmed arterial
hypertension (>200/110 mm Hg)
at entry were also not included in
this study. Each patient received
a total dose of 20 units Retelex
within 6 hours after the onset of
acute myocardial infarction (AMI)
symptoms. The dose was given as
two 10 unit Intravenous injections
each over two minutes, no more
than 30 minutes apart. Patients
were followed on day 1, 3, 5/7 and
30.
Evaluation criteria: The primary
evaluation criteria was total number
of patients showing clinically
successful thrombolysis based on
50% resolution of ST-elevation in the
maximum affected (adjacent) leads
within 90-120 minutes of initiation
of Reteplase and resolution of chest
pain. Secondary evaluation criteria
included percentage of patient
requiring rescue PCI, percentage
of patients who underwent
planned angioplasty or coronary
artery bypass graft (CABG) after
thrombolysis. In addition, door
to needle time (ECG diagnosis of
STEMI and first dose of Retelex)
and concomitant medication were
also recorded for patients receiving
Reteplase. Repeat ECG was taken
within 90 to 120 min after initiation
of Retelex (Reteplase). Global
assessment of efficacy and safety
was done by patient as well as
i n ve s t i g a t o r . T h e e f f i c a c y wa s
rated on 4 point (excellent, good,
moderate, poor ) while safety was
rated on 3 points (good, moderate,
poor). Safety was assessed through
recording all adverse events.
Statistical analysis: Mean and
percentage were calculated for
primary efficacy parameters i.e.
50% resolution of ST elevation and
resolution of chest pain. Chi square
test was used for comparing the
difference between diabetes versus
non-diabetes patients for primary
efficacy variables as well as for
comparing the number of patients
 Journal of The Association of Physicians of India Vol. 63 April 2015 33

Table 1 : Baseline characteristics 100.00%

90.50%
95.40%

(n=228) 90.00%

Mean age (SD) 58.65 (11.69) years 80.00%

Male (%) 176 (77.2%) 70.00%

% of patients
Female (%) 52 (22.8%) 60.00%
50% resolution of ST elevation
50.00% Resolution of chest pain
Table 2 : Diagnosis of enrolled patients 40.00%

Diagnosis N (%) 30.00%

ST-elevated anterior wall MI 157 (68.9%) 20.00%

9.50%
ST-elevated inferior wall MI 71 (31.1%) 10.00%
4.60%

ST-elevated posterior wall MI 22 (9.6%) 0.00%

Other 37 (16.2%) Yes No

requiring rescue PCI, angioplasty Fig. 1 : Primary efficacy parameters

and CABG between diabetes versus 60% 56%
non-diabetes patients. ANOVA was 53.6%

used for evaluating the difference 50%

in vital parameters compared to
baseline. 40%
39.6% 49.20%
% of patients

Results Patient
30%
Investigator
A total of 228 patients were
enrolled in this study out of 20%

which 140 patients had diabetes

mellitus. Table 1 shows the baseline 10%
4.30%
3.6%
characteristics of patients enrolled 0.8% 1.30%

in the study. The age range of 0%

Excellent Good Moderate Poor
patients was from 27 years to 89
years. Maximum enrolled patients Fig. 2: Overall global assessment of efficacy
(68.9%) had ST elevated anterior 100%
100%
wall myocardial infarction followed 92%
by inferior wall and posterior wall 100%
83%
myocardial infarction (Table 2). 90%

Efficacy: As shown in Figure 80%

1, 50% resolution of ST elevation
70%
(n=221) was seen in 90.50% patients
% of patients

while resolution of chest pain 60%

(n=216) was reported in 95.4% 50%
patients. No significant difference
40%
was seen in number of patients
with 50% resolution of ST elevation 30%
b e t we e n d i a b e t e s ve r s u s n o n -
20%
diabetes patients (p=0.1538 for 50%
ST elevation resolution, p=0.4031 10%

resolution of chest pain). 0%

Overall (n=211) only 7.6% Aspirin Clopidogrel LMWH/Heparin Statin

patients required rescue PCI

Fig. 3 : Most commonly used concomitant medicines
while 22% and 16.8% patients
underwent angioplasty (n=200) Table 3: Mean changes in the vital parameters
and CABG (n=191), respectively.
Duration SBP (mm Hg) DBP (mm Hg) Pulse rate (/min) Respiratory rate (/min)
No significant difference was seen (days) n=187 n=186 n=185 N=175
in diabetes versus non-diabetes 1 147.13 + 27.84 89.62 + 17.49 81.88 + 16.42 22.78 + 06.67
patients requiring rescue PCI 3 *133.37 + 19.05 *83.01 + 10.86 *76.88 + 08.39 *20.98 + 05.15
(p=0.1059), angioplasty (p=0.2172) 5/7 *124.29 + 12.85 *80.26 + 09.65 *74.71 + 07.20 *20.03 + 04.91
and CABG (p=0.9128). 30 *121.64 + 11.24 *79.27 + 06.98 *74.16 + 06.88 *19.88 + 04.80
Global assessment of efficacy: P value *P < 0.05 P < 0.05 *P < 0.05 *P < 0.05
As per the global assessment of
 34 Journal of The Association of Physicians of India Vol. 63 April 2015
100.0% 94.3% 94.00%
90.0%
80.0%
70.0%
% of patients
60.0%
50.0%
40.0%
30.0%
20.0%
10.0%
0.0%
Good
Fig. 4 : Overall global assessment of tolerability
efficacy, excellent to good efficacy
was reported by 95.6% and 93.8%
of patients as evaluated by patients
(n=225) and investigators (n=224),
respectively (Figure 2).
The most commonly used
concomitant medications in the
study included aspirin, clopidogrel,
LMWH/Heparin and statin (Figure
3). Sorbitrate was used by 9.1%
patients.
Effect on vital parameters: As
compared to baseline, significant
reduction was seen in the vital
parameters i.e. blood pressure,
pulse rate and in respiratory rate
(Table 3). The mean door to needle
time was 24.93 (25.57) minutes in
all cases.
Safety assessment: A total of 12
patients (5.3%) patients reported
adverse event. Arrhythmia,
epistaxis, hematuria, ventricular
fibrillation and VT were the
adverse events reported in the
study. No significant difference
was seen in adverse event rate
b e t we e n d i a b e t e s ve r s u s n o n -
diabetes patients (p>0.05).
Global assessment of
tolerability: As per the global
assessment of tolerability, good to
moderate tolerability was reported
by 99% patients as evaluated by
patients (n=208) whereas 100%
patients reported good to moderate
tolerability as evaluated by
investigators (n=215), respectively
(Figure 4). No significant difference
was seen in the tolerability as
reported by patients or doctors
in diabetes versus non-diabetes
Patient
Investigator
6.00%
4.3%
1.0%
Moderate Poor
patients (p=0.5641 for evaluation
by investigator; p=0.8832 for
evaluation by patients).
Discussion
Thrombosis is part of the normal
physiologic haemostatic response
to limit bleeding in case of vascular
injury. Usually thrombus remains
at the site of injury and does
not limit the blood flow. Under
some circumstances, the thrombus
c a n o c c l u d e t h e b l o o d ve s s e l .
Acute myocardial infarction is one
such acute thrombotic occlusive
disorder. ST elevated myocardial
infarction needs immediate
treatment. Thrombolytic treatment
should be started as soon as possible
to delay the complications. In this
study, the door to needle time was
less than half an hour i.e. 24.93
minutes.
A fibrin-specific agent has class
IA recommendation from the
European Society of Cardiology
guidelines for the management of
STEMI.10 Reteplase, a plasminogen
activator has been well studied in
the management of ST elevated
myocardial infarction both globally
as well as in India. Internationally,
in large randomized clinical trials in
patients with STEMI, reteplase was
found to be superior to alteplase
for coronary artery patency at
60 and 90 minutes. 8 Similarly in
another study with reteplase,
7 3 . 7 5 % p a t i e n t s a c h i e ve d 5 0 %
lowering of ST segment elevation at
6 hours 11 while in our study, 90.5%
patients achieved 50% reduction
of ST elevation. Similarly large
number of patients (95.4%) also
had resolution of chest pain. In
a n I n d i a n o b s e r va t i o n a l s t u d y
with tenecteplase resolution of
chest pain was reported in 93.65%
patients receiving tenecteplase. 4
In this study, all the patients had
received in-hospital tenecteplase
as per weight-adjusted dosing. 4
T h e a d va n t a g e o f R e t e p l a s e i s
its simple dosing schedule i.e.
two 10 unit intravenous bolus
injections each over two minutes,
no more than 30 minutes apart.
The bolus injection with reteplase
is possible because of its long
half-life compared to alteplase.
The half-life of reteplase is four
times longer than alteplase. Studies
in animal have suggested that
double bolus regimen is preferable
to doubling the single bolus dose
of reteplase. The suggested time
interval of 30 minutes between
two injections is derived from the
pharmacokinetic modelling. 9 No
statistically different difference
wa s s e e n c l i n i c a l l y s u c c e s s f u l
thrombolysis with tenecteplase in
diabetics versus non-diabetics. 4
Similarly, we also did not observe
s i g n i f i c a n t d i f f e r e n c e b e t we e n
diabetes and non-diabetes
patients with reteplase. It is also
documented in a comparative data
that reteplase achieves higher and
faster reperfusion after two bolus
injections of 10 units than 100 mg
infusion of alteplase. 12
Reteplase was well tolerated
by patient in this study. On
global assessment of tolerability,
none of the patient reported
poor tolerability as evaluated by
investigators. Thus, proven efficacy
and safety finding from this study
demonstrates utility of reteplase in
Indian patients with STEMI.
Reteplase is a better fibrinolysis
agent because of its multiple
advantages including lesser amount
of drug required to maintain
t h e r a p e u t i c l e ve l , 1 3 p r o l o n g e d
half life (13-16 min) 14 and easy
administration as no infusion
required. The recommended

dosage for reteplase is two IV
bolus doses of 10 U over 2 min, 30
min apart. 9 Unlike tenectaplase, 15
the dosing regimen is non-weight-
based. The simple dosing regimen
has potential to reduce fibrinolytic
dosing errors resulting in improved
outcome. Reteplase has enhanced
thrombolytic and antithrombotic
potency due to reversible binding,13
comparatively low fibrin binding 14
which improves clot penetration
and high resistance to inhibition
by plasminogen activators. It is
less effective in lysing platelet rich
plasma clots and aged clots 16 as
haemostatic plugs are thought to
be older clots that seals small vessel
wall injuries.
Conclusion
Reteplase IV Injection-
recombinant plasminogen activator
is effective and well tolerated in
the management of ST elevated
myocardial infarction (STEMI) in
Indian patients including diabetes
patients.
Acknowledgement
The authors of this study
wish to thank Dr. Anant D Patil
for assistance in writing the
manuscript.
Journal of The Association of Physicians of India Vol. 63 April 2015
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