Está en la página 1de 5

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 is a plasminogen activator which The patients with unexplained


mimics endogenous tissue puncture in a non-compressible

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


90.0% number of patients (95.4%) also
80.0% had resolution of chest pain. In
70.0%
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
% of patients

60.0%
Patient chest pain was reported in 93.65%
50.0%
Investigator patients receiving tenecteplase. 4
40.0%
In this study, all the patients had
30.0%
received in-hospital tenecteplase
20.0%
6.00%
as per weight-adjusted dosing. 4
10.0% 4.3%
1.0% T h e a d va n t a g e o f R e t e p l a s e i s
0.0% its simple dosing schedule i.e.
Good Moderate Poor
two 10 unit intravenous bolus
Fig. 4 : Overall global assessment of tolerability injections each over two minutes,
no more than 30 minutes apart.
efficacy, excellent to good efficacy patients (p=0.5641 for evaluation The bolus injection with reteplase
was reported by 95.6% and 93.8% by investigator; p=0.8832 for is possible because of its long
of patients as evaluated by patients evaluation by patients). half-life compared to alteplase.
(n=225) and investigators (n=224), The half-life of reteplase is four
respectively (Figure 2). Discussion
times longer than alteplase. Studies
The most commonly used Thrombosis is part of the normal in animal have suggested that
concomitant medications in the physiologic haemostatic response double bolus regimen is preferable
study included aspirin, clopidogrel, to limit bleeding in case of vascular to doubling the single bolus dose
LMWH/Heparin and statin (Figure injury. Usually thrombus remains of reteplase. The suggested time
3). Sorbitrate was used by 9.1% at the site of injury and does interval of 30 minutes between
patients. not limit the blood flow. Under two injections is derived from the
Effect on vital parameters: As some circumstances, the thrombus pharmacokinetic modelling. 9 No
compared to baseline, significant c a n o c c l u d e t h e b l o o d ve s s e l . statistically different difference
reduction was seen in the vital Acute myocardial infarction is one 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
parameters i.e. blood pressure, such acute thrombotic occlusive thrombolysis with tenecteplase in
pulse rate and in respiratory rate disorder. ST elevated myocardial diabetics versus non-diabetics. 4
(Table 3). The mean door to needle infarction needs immediate Similarly, we also did not observe
time was 24.93 (25.57) minutes in treatment. Thrombolytic treatment 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
all cases. should be started as soon as possible diabetes and non-diabetes
Safety assessment: A total of 12 to delay the complications. In this patients with reteplase. It is also
patients (5.3%) patients reported study, the door to needle time was documented in a comparative data
adverse event. Arrhythmia, less than half an hour i.e. 24.93 that reteplase achieves higher and
epistaxis, hematuria, ventricular minutes. faster reperfusion after two bolus
fibrillation and VT were the injections of 10 units than 100 mg
A fibrin-specific agent has class
adverse events reported in the infusion of alteplase. 12
IA recommendation from the
study. No significant difference European Society of Cardiology Reteplase was well tolerated
was seen in adverse event rate guidelines for the management of by patient in this study. On
b e t we e n d i a b e t e s ve r s u s n o n - STEMI.10 Reteplase, a plasminogen global assessment of tolerability,
diabetes patients (p>0.05). activator has been well studied in none of the patient reported
Global assessment of the management of ST elevated poor tolerability as evaluated by
tolerability: As per the global myocardial infarction both globally investigators. Thus, proven efficacy
assessment of tolerability, good to as well as in India. Internationally, and safety finding from this study
moderate tolerability was reported in large randomized clinical trials in demonstrates utility of reteplase in
by 99% patients as evaluated by patients with STEMI, reteplase was Indian patients with STEMI.
patients (n=208) whereas 100% found to be superior to alteplase Reteplase is a better fibrinolysis
patients reported good to moderate for coronary artery patency at agent because of its multiple
tolerability as evaluated by 60 and 90 minutes. 8 Similarly in advantages including lesser amount
investigators (n=215), respectively another study with reteplase, of drug required to maintain
(Figure 4). No significant difference 7 3 . 7 5 % p a t i e n t s a c h i e ve d 5 0 % 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
was seen in the tolerability as lowering of ST segment elevation at half life (13-16 min) 14 and easy
reported by patients or doctors 6 hours 11 while in our study, 90.5% administration as no infusion
in diabetes versus non-diabetes patients achieved 50% reduction required. The recommended
Journal of The Association of Physicians of India Vol. 63 April 2015 35

dosage for reteplase is two IV References G. Current Clinical Use of Reteplase


for Thrombolysis. A Pharmacokinetic-
bolus doses of 10 U over 2 min, 30
1. Shah B and Mathur P. Surveillance of Pharmacodynamic Perspective. Clin
min apart. 9 Unlike tenectaplase, 15
cardiovascular disease risk factors in India: Pharmacokinet 1999; 4:265-276.
the dosing regimen is non-weight-
The need & scope. Indian J Med Res 2010; 10. The task force on the management of
based. The simple dosing regimen 132:634-642. ST-segment elevation acute myocardial
has potential to reduce fibrinolytic infarction of the European Society
2. Gupta R. Burden of coronary heart disease
dosing errors resulting in improved in India. Indian Heart J 2005; 57:632-8. of Cardiology. Management of acute
outcome. Reteplase has enhanced 3. Burden of disease in India, Background
myocardial infarction in patients presenting
thrombolytic and antithrombotic with persistent ST-segment elevation. Eur
papers for the National Commission on
Heart J 2008; 29:2909-45.
potency due to reversible binding,13 Macroeconomics. New Delhi: Ministry of
comparatively low fibrin binding 14 Health and Family Welfare, Government 11. Shah K, Apsangikar P, Allu J, Chaudhry S.
of India; 2005. Clinical Retrospective and Prospective
which improves clot penetration Evaluation of Efficacy and Safety of
and high resistance to inhibition 4. Iyengar SS, Nair T, Hiremath JS, et al. Efficacy
Reteplase in STEMI Patients. Indian Medical
by plasminogen activators. It is & safety of Tenecteplase in 6000 patients
Gazette 2012; 479-487.
with ST-elevation myocardial infarction
less effective in lysing platelet rich from the Elaxim Indian Registry. Indian 12. Smalling RW, Bode C, Kalbfleisch J, et al.
plasma clots and aged clots 16 as Heart J 2011; 63:104-107 More rapid, complete and stable coronary
haemostatic plugs are thought to 5. Vaishnav A. Vaishnav A, Khandekar S,
thrombolysis with bolus administration of
reteplase compared with alteplase infusion
be older clots that seals small vessel Vaishnav S. Pre-hospital thrombolysis. J
in AMI. RAPID investigators. Circulation
wall injuries. Assoc Physicians India 2011; 59Suppl:14-18.
1995; 91:2725-2732.
6. Kushner FG, Hand M, Smith SC, et al. 2009
Conclusion Focused Updates: ACC/AHA Guidelines
13. Smalling RW. Pharmacological and clinical
impact of the unique molecular structure
for the Management of Patients With ST-
of a new plasminogen activator. European
Reteplase IV Injection- Elevation Myocardial Infarction. J Am Coll
Heart Journal 1997; 18{Supplement F),Fl
recombinant plasminogen activator Cardiol 2009; 54;2205-2241.
1-F16.
is effective and well tolerated in 7. Armstrong PW; WEST Steering Committee.
14. Weaver WD. Results of the RAPID 1 and
the management of ST elevated A comparison of pharmacologic therapy
RAPID 2 thrombolytic trials in acute
myocardial infarction (STEMI) in with/ without timely coronary intervention
myocardial infarction. European Heart
vs. primary percutaneous intervention
Indian patients including diabetes Journal 1996; 17{Supplement E):14-20.
early after ST-elevation myocardial
patients. infarction: the WEST (Which Early ST- 15. Angeja BG, Alexander JH, Chin R, et al.
elevation myocardial infarction Therapy) AngeSafety of the weight-adjusted dosing
Acknowledgement study. Eur Heart J 2006;27:13:1530-8. regimen of tenecteplase in the ASSENT-
Trial. Am J Cardiol 2001;88:1240-5
8. Simpson D, Siddiqui MAA, Scott LJ,
The authors of this study Hilleman DE. Reteplase. A Review of its 16. Martin U, Sponer G, Strein K. Differential
wish to thank Dr. Anant D Patil Use in the Management of Thrombotic fibrinolytic properties of the recombinant
for assistance in writing the Occlusive Disorders. Am J Cardiovasc Drugs plasminogen activator BM 06022 in human
plasma and blood clot systems in vitro.
manuscript. 2006; 4:265-285.
Blood Coagul Fibrinolysis 1993; 4:235-42.
9. Martin U, Kaufmann B, Neugebauer