Effects
of Low Molecular Weight Heparin on patients with unstable
angina pectoris (JIPAILIN vs. Fraxiparine)
LIANG
Yan and WU
Haiying
Chinese
Academy of Medicine, Union Medical University of China,
Cardiovascular Institute and FU Wai Heart Hospital, Beijing
100037, China
ABSTRACT
[Objective] To study the clinical effect and side-effect
of domestic Low Molecular Weight Heparin (JIPAILIN) comparing
with Fraxiparine on patients with unstable angina pectoris
[Methods] This is a prospective, randomized single-blind
study. 50 patients with unstable angina pectoris were
randomized to receive JIPAILIN or Fraxiparine twice-daily
subcutaneous injection for 5 days according to body weight.
The effects of JIPAILIN and Fraxiparine in reducing cardiac
affair, relieving angina and laboratory monitoring were
observed and compared. [Results] Totally 50 patients were
enrolled. During 30-day’s follow up, there was no re-infarction
or death. Recurrent angina rates of JIPAILIN and Fraxiparine
groups were 44% and 48% (P=0.777), respectively. The effect
of relieving angina in JIPAILIN group was similar with
that in Fraxiparine group (96% vs. 92%, P=0.552), and
the side effects have no significant difference. [Conclusion]
Combining with traditional therapy, JIPAILIN has the same
effects as Fraxiparine on deceasing heart events and relieving
angina. The side effects were similar between these two
groups. Moreover JIPAILIN has lower price.
Key
words: Low Molecular Weight Heparin (LMWH), unstable
angina pectoris, acute non-Q wave myocardiac infarction
In recent years, the status of applying Low Molecular
Weight Heparin to unstable angina pectoris has been elevated,
due to its strong anti-Xa activity, lower bleeding risk,
higher bioavailability, longer half time and no requirement
of laboratory monitoring at common doses [1,2], as well
as its simplicity during administration. Clinically LMWH
has been replacing UFH (unfractionated heparin) gradually.
Our study compared the efficacy and safety of JIPAILIN,
a domestic LMWH of Hangzhou Jiuyuan Gene Engineering Co.,
Ltd. and Fraxiparine, an imported LMWH of Sanofi France,
in the treatment of unstable angina pectoris.
Objects
and Methods
Objects:
Diagnosed as unstable angina according to <<American
Cardiology>> 1999 version, angina attack within
48 hours before enrollment, ischemic ST-T change in ECG,
age≤75, without acute mycardiac infarction,
without anticoagulation contraindication, without UFH
or LMWH administration in 24 hours before enrollment.
Methods:
This is a prospective, randomized, single-blind study.
Patients were randomized into JIPAILIN and Fraxiparine
groups. In addition to regular treatment including nitroglycerin,
calcium antagonist, beta-receptor blocker and aspirin,
patients received LMWH treatment the next morning based
on their body weight (<60 Kg JIPAILIN 0.41ml equivalent
to 4100 anti-Xa IU or Fraxiparine 0.4ml equivalent to
4100 anti-Xa IU; ≥60 Kg JIPAILIN 0.6ml equivalent to 6100
anti-Xa IU or Fraxiparine 0.6ml equivalent to 6150 anti-Xa
IU) s.c. once per 12 hours for consecutively 5 days, followed
up by 30 days (including 5 days of LMWH administration
and 25 days after administration). No limitation was imposed
on coronary angiography or special interference procedure
(like PTCA or CABG), but angina data were collected until
interference procedure applied.
The
severity of angina was classified according to “National
conference on angina pectoris and myocardiac ischemia
2000”[3] as high, medium and low-risk groups. Many indexes
were observed between JIPAILIN and Fraxiparine groups
and between pre-treatment (48 hours before LMWH treatment)
and post-treatment in the same group, including: number
of angina attack, lasting time of angina, nitroglycerin
consumption, mortality, re-infarction and bleeding. Blood
pressure, heart rate and ECG change were monitored during
the period. Blood-urine-feces routine, hepatic and renal
function, CK & MB-CK and coagulation were observed
before LMWH administration and the first day after LMWH
termination.
Evaluation
of curative effect: based on the criteria of phase II
clinical efficacy of anti-angina agents by Ministry of
Health, whereas no angina or number of angina attack reduced
by over 80%, consumption of nitroglycerin reduced by over
80% were classified as “Excellent”; number of angina attack
and consumption of nitroglycerin reduced by 50% to 80%
were classified as “effective”; number of angina attack
and consumption of nitroglycerin reduced by less than
50% were classified as “invalid”. All data were expressed
with mean±SD and were analyzed by t test and x2 test.
Results
Patient
conditions
Totally
50 patients were enrolled and randomized into JIPAILIN
and Fraxiparine groups, 25 in each group. There was no
significant difference in gender, age, type of angina
and heart function (see table 1). Severity of unstable
angina were: in JIPAILIN group, high risk 10 cases, medium
risk 8 cases, low risk 7 cases; in Fraxiparine group,
high risk 13 cases, medium risk 8 cases and low risk 4
cases. There was no significant difference between the
two groups (x2=1.209, P=0.546).
Disease
history: In JIPAILIN/Fraxiparine groups, the data were:
coronary disease 20/23 cases, hypertension 11/17 cases,
hyperlipidemia 13/12 cases, diabetes 8/2 cases, cerebral
apoplexy 3/1 cases, smoking 18/14 cases (of which 7/9
cases quitted smoke). The conditions were similar between
the two groups therefore offering comparability. Before
LMWH administration, 22 cases (88%) in JIPAILIN group
and 24 cases (96%) in Fraxiparine group had received combination
therapy including nitroglycerin, calcium antagonist, beta-receptor
blocker and Aspirin, without significant difference between
the two groups (x2=1.087, P=0.297).
Table
1. Comparison of patient conditions
| |
Age1(years)
|
Gender2
|
Angina
type3
|
Heart
function (NYHA)4
|
|
male
|
female
|
Tiredness & idiopathetic
|
tiredness
|
idiopathetic
|
I
|
II
|
III
|
IV
|
|
JIPAILIN
(n=25)
|
58.3±11.2
|
16
|
9
|
19
|
4
|
2
|
13
|
12
|
0
|
0
|
|
Fraxiparine
(n=25)
|
61.3±10.3
|
18
|
7
|
19
|
5
|
1
|
10
|
11
|
4
|
0
|
t
test, p=0.346
x2=0.444,
P=0.544
3.
x2=0.444, P=0.931
4.
x2=0.435, P=0.109
Special
procedures
During
observation period, traumatic procedures were of relatively
high rate, e.g., 44 cases (JIPAILIN 21 case, 85%; Fraxiparine
23 cases, 92%) received coronary angiography(CA), all
with clear coronary pathologic changes, further proving
the accuracy and reliability of patient enrollment. In
the observation period, 1 case in JIPAILIN group and 2
cases in Fraxiparine group (P=0.552) acutely received
PTCA or CABG procedure due to seriousness of pathologic
changes or symptoms. Fourteen cases in JIPAILIN group
and 13 cases in Fraxiparine group received PTCA or CABG
procedures during the follow up period, without significant
difference found between the two groups.
Evaluation
of curative effects
Number
of angina attack, angina lasting time and nitroglycerin
consumption were compared before LMWH administration (48
hours before) and after LMWH administration (within follow
up period, terminate counting when interference procedure
applied). The above-mentioned 3 indexes were significantly
reduced in both groups after LMWH administration (P<0.0007).
Based
on the criteria of MOH, in JIPAILIN group, 20 cases were
evaluated as “excellent”, 4 as “effective”, 1 as “invalid”
whereas in Fraxiparine group, 20 cases were evaluated
as “excellent”, 3 as “effective”, 2 as “invalid” (x2=0.476,
P=0.788). Total efficacy rate (including “excellent” and
“effective”) were 96% and 92% for JIPAILIN and Fraxiparine
group, respectively. These demonstrate that the administration
of JIPAILIN or Fraxiparine together with traditional therapies
are effective in relieving unstable angina pectoris symptoms,
with no significant difference found between the two drugs.
Table
2. Comparison of angina between JIPAILIN and Fraxiparine
groups
|
Pre-administration
|
Angina
frequency (/day)
|
Angina
lasting time (mins/day)
|
Consumption
of nitroglycerine (tablets/day)
|
|
JIPAILIN
group
|
1.327±0.998
|
11.813±10.813
|
1.087±0.999
|
|
Fraxiparine
group
|
1.480±0.996
|
8.920±6.450
|
1.707±1.422
|
|
P
value
|
0.589
|
0.258
|
0.081
|
|
After
administration
|
Average
observation time (days)
|
Angina
frequency (/day)
|
Angina
lasting time (mins/day)
|
Consumption
of nitroglycerine (tablets/day)
|
|
JIPAILIN
|
14.20±9.548
|
0.178±0.339
|
1.516±4.349
|
0.251±0.799
|
|
Fraxiparine
|
16.24±8.531
|
0.236±0.513
|
0.959±2.142
|
0.352±0.808
|
|
P
value
|
0.430
|
0.637
|
0.569
|
0.549
|
4.
Major events
In
the 30 day observation period, death and re-infarction
rates were both zero; 11 case in JIPAILIN group and 12
cases in Fraxiparine group (44%: 48%, P=0.777) reported
recurrent angina; regarding adverse reactions, 1 bleeding
(slight nasal mucosa) reported in JIPAILIN group and 1
(moderate, at coronary puncture site) reported in Fraxiparine
group, both were without necessity to terminate drug administration.
Laboratory
monitoring
Blood
indexes including WBC, RBC, Plt, BUN, Cr, GPT, GOT, CK,
MB-CK, LDH, LDH1, TNT, APTT, PTT, PTA, INR, Fib, as well
as urine and feces routine were observed before and on
the first day after drug administration. There was no
significant difference found between the two groups before
drug administration (P>0.05). After drug administration,
in JIPAILIN group, GPT increased from 33.7±23.7 IU/L to 48.9±30.9
IU/L (P=0.0565, no statistical significance), GOT increased
from 26.5±14.1 IU/L to 40.8±19.2 IU/L (P=0.0041), 13 cases reported GPT and/or
GOT increase (to 42~116 IU/L) due to drug administration;
2 cases reported WBC decrease (to 3.66~3.8x109/L,
P>0.1), non reported Plt decrease; no change in other
indexes (0.121<P<0.981); urine and feces blood were
both negative. After drug administration, in Fraxiparine
group, GPT increased from 26.5±11.3 IU/L to 55.4±35.7 IU/L (P=0.0006), GOT increased from 26.4±6.9 IU/L to 43.5±24.4 IU/L (P=0.0022), 13 cases reported GPT and/or
GOT increase (to 42~146 IU/L) due to drug administration;
3 cases reported WBC decrease (to 3.4~3.7x109/L,
P>0.1); one case reported Plt decrease (to 71x109/L,
P>0.1); no change in other indexes (0.111<p<0.889);
1 case reported urine blood; 1 case reported CK and CK-MB
increase after drug administration (CK 50.4 to 1049.0
IU/L, CK-MB 6 to 81 IU/L). The results demonstrate that
both JIPAILIN and Fraxiparine have slight impact on liver
function whereas both have no significant effects on blood
routine, renal function, CK & MB-CK and coagulation
indexes; only one possible myocardial injury occurred
in Fraxiparine group.
Discussion
LMWHs
are produced by chemical or enzymic depolymerization of
UFH, with average molecular weight (M.W.) between 4000
to 6500 Daltons. The lower M.W. leads to higher ratio
of anti-Xa: anti-IIa, less likely to be inactivated by
platelet factor 4 (PF4), resulting in better anticoagulation
effect. LMWHs have low affinity to plasma proteins, better
bioavailability and predictable dose-effect profile, as
well as longer plasma half time and simpler clinical administration.
FRISC [4] found, comparing to placebo, administration
of LMWH for 6 days to patients of acute coronary artery
disease could significantly decrease mortality and infarction
rate (4.8% and 1.8%, P<0.05), the effect remained even
after 40 days. In ESSENCE [5] patients of unstable angina
pectoris and non-Q wave myocardiac infarction were randomized
into LMWH and UFH groups, with an average drug administration
time of 3.1 days, the cardiac affairs rate at day 14 was
significantly lower in the former group (16.6% vs. 19.8%,
P<0.05), the effect remained even after 30 days. Therefore,
the effect of LMWHs in treating unstable angina pectoris
and non-Q wave myocardiac infraction has been internationally
recognized. Fraxiparine is one of the earliest LMWH preparation
applied clinically. Fraxiparine is a preparation of low
molecular glucosaminoglycans (calcium salt) manufactured
by nitrous acid depolymerization followed by purification.
Fraxiparine has an average M.W. about 4500, in vitro anti-Xa:
anti-IIa ratio of 4:1, which acts mainly by inhibiting
thrombin as well as dissolving thrombus. Fraxiparine acts
in a quick and lasting way, with half life at 4 hours
when administered subcutaneously. Therapeutic dose of
Fraxiparine does not induce coagulation or prolong APTT.
JIPAILIN is a preparation of glucosaminoglycans (sodium
salt), also manufactured by nitrous acid depolymerization,
with an average M.W. of about 4000, anti-Xa: anti-IIa
ratio of 3~4:1, half life of 4~5 hours when administered
subcutaneously, without prolonging APTT.
The
characteristics of JIPAILIN and Fraxiparine are similar
and therefore afford comparability. According to our observation,
JIPAILIN and Fraxiparine have the same efficacy and similar
side effects, whereas the former has lower price and therefore
afford better Price/Effect ratio. We propose JIPAILIN
to be used widely, which is beneficial for reducing cost
induced during hospitalization.
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