The treatment groups
were well-balanced regarding demographic characteristics. Nearly all (>94%)
of the patients were Caucasian and there were more females (62%) than males
(38%).
Approximately two-thirds
of patients were 65 years or older (66%) although there was a
wide range of ages in
the program (24 to 91 years of age). There were 18% to 20% of patients above
100 kgs and about 50% with a BMI >30 kg/m2 . A total of 16
patients had severe renal impairment (CrCL <30 mL/min) (in violation of
entry criteria). Approximately 35% of the patients had some renal impairment
(CrCL <80 mL/min).
1.1 Most common AEs –Warfarin-comparison Pool
Overall, more than 55%
of patients in each treatment group experienced at least 1 AE. The frequency of
AEs was similar in the ximelagatran 24-mg and the warfarin groups (66% and 61%,
respectively). The frequency of AEs was similar in the ximelagatran 36-mg and
the warfarin groups (58% and 56%, respectively).
The incidence of SAEs
was higher in the ximelagatran treatment groups than in the concurrent warfarin
group (3.8 vs. 3.2% for 36 mg of ximelagatran vs. warfarin and 3.2% vs. 2.7%
for 24 mg of ximelagatran vs. warfarin).
The incidence of
discontinuations was higher in the ximelagatran treatment groups than in the
concurrent warfarin group (2.6% vs. 2.0% for 36 mg of ximelagatran vs. warfarin
and 3.1% vs. 2.1% for 24 mg of ximelagatran vs. warfarin respectively).
1.2 Deaths
There were 18 fatal
cases in the Warfarin-comparison Pool (12 patients exposed to ximelagatran and
6 patients exposed to warfarin) with 4 and 3 fatalities occurring during the
treatment period,
respectively.
Of the 12 fatal SAEs
reported among the 3010 patients who received ximelagatran (0.4%), 2 were fatal
bleeding events (both on ximelagatran 36 mg).
Six were fatal events in which ‘PE could not be excluded’. The last 4
fatal SAEs in patients who received ximelagatran were adjudicated as ‘death not
associated with VTE or bleeding’. The
investigators reported the causes of death in 1 patient on treatment as sudden
death, and in the other 3 patients after treatment as intestinal perforation,
acute myocardial infarction, and pneumonia.
Of the 6 fatal SAEs
reported among the 2226 patients who received warfarin (0.3%), 2 were fatal
events in which ‘PE could not be excluded’. The last 4 fatal SAEs in
warfarin-treated patients were adjudicated as ‘death not associated with VTE or
bleeding’. The investigators reported
the causes of death in 2 patients on treatment as arrhythmia and MI and in the
other 2 after treatment as colon carcinoma and acute myocardial infarction.
Two fatal cases of GI
hemorrhage occurred during treatment in the ximelagatran 36-mg group. The
number and percentage of patients who died during or after treatment in the
Warfarin-comparison Pool is presented in Table 8.
Table 8: Number (%) of patients with fatal SAEs
during or after treatment, presented by preferred term: The Warfarin-
comparison Pool (exposed safety population)
1.3 Serious Adverse Events other than deaths –
Warfarin-comparison Pool
Within both 36-mg
(EXULT) and 24-mg pools, the frequency of non-fatal SAEs was higher in either
ximelagatran treatment group (3.7% and 3.5%) than in their respective warfarin
groups (3.1 and 2.6%) during treatment.
Including both during
study treatment and after study treatment periods, the most frequently
occurring non-fatal SAEs were postoperative complications and myocardial
infarction, which occurred more frequently in the ximelagatran groups, and
atrial fibrillation, which occurred more frequently in the warfarin group.
The number of patients
with the most commonly reported non-fatal SAEs during and after
treatment is presented
in Table 9.
Table 9 Number (%) of patients with the most
commonly reported non- fatal SAEs during and after treatment: The Warfarin-
comparison Pool (exposed safety population)
Please see the section
of 1.7: coronary artery disease adverse events for more details about the
adverse events related to myocardial infarction and coronary artery diseases.
1.4 Discontinuations due to AEs -
Warfarin-comparison Pool
Discontinuations due to
AEs (DAE) were slightly higher in the ximelagatran 36-mg group (2.6%) than
warfarin (2.0%) as well as in the ximelagatran 24-mg group comparison to
warfarin (3.1% versus 2.1%, respectively); this was driven by an excess of
bleeding-related AEs. Regardless of treatment group, the most common reason for
a DAE was postoperative complication, with a similar incidence between
treatment groups.
1.5 Bleeding events in the Warfarin-comparison Pool
Major bleeding events
were uncommon overall and higher in ximelagatran groups than warfarin groups
during the treatment period (0.9% ximelagatran 36 mg, 0.5% warfarin; 0.9%
ximelagatran 24 mg, 0.6% warfarin). In the 36-mg Pool, the difference in the
frequencies of major bleeding events between ximelagatran and warfarin was 0.4%
(95% CI, –0.1% to1.0%). Similar results were noted for the 24-mg Pool
(ximelagatran-warfarin, 0.3%; 95% CI, -0.5% to 1.0%). The proportions of
patients with on-treatment major bleeding events in the Warfarin-comparison
Pool, for both the 36-mg and 24-mg Pools, are summarized in Table 10.
Table 10 Number (%) of patients with on-
treatment adjudicated major bleeding events: Warfarin- comparison Pool (exposed
safety population)
bleeding event and/or
bleeding index >2. The distribution of all major bleeding events by
adjudication criteria was similar to the distribution of on-treatment events.
In the 36-mg Pool, the
most common locations of on-treatment major bleeding events in the ximelagatran
group were wound hematoma, gastrointestinal bleeding, and wound bleeding.
Events in these locations occurred with comparable frequency in the warfarin
group. In the 24-mg Pool, wound hematoma and gastrointestinal bleeding were
more frequent in the ximelagatran group than in the warfarin group, while wound
bleeding occurred only in the warfarin group. There were no major nasal or
urinary bleeding events in any treatment group.
The frequencies of
patients with on-treatment major/minor bleeding events were higher in
ximelagatran groups than warfarin groups (5.1% ximelagatran 36 mg, 4.1%
warfarin; 5.7%
ximelagatran 24 mg, 4.7%
warfarin).
Two fatal on-treatment
major bleeding events occurred in the ximelagatran 36-mg group; both
events were coded as GI
hemorrhage. None of the on-treatment major bleeding events in the ximelagatran 24-mg group was fatal. There were no fatal on-treatment
bleeding events in the warfarin-groups.
Two critical-site
on-treatment bleeding events occurred during ximelagatran treatment (0.9%).
One patient
(SH-TPO-0012-029-10779) treated with ximelagatran 36 mg developed postoperative
confusion just after surgery. A CT scan revealed a subdural hematoma. The other
patient (SH-TPO-0010-016-2131), who was treated with ximelagatran 24 mg, was
found by CT scan to have a left frontal brain hemorrhage after 6 days of
postoperative confusion; a biopsy
revealed a malignant
glioma; the reported AE was coded as cerebral hemorrhage. No
bleeding at other
critical sites (intraspinal, intraocular, retroperitoneal, or pericardial) was
reported in the
ximelagatran groups. None of the major bleeding events reported in warfarin-treated
patients occurred at a critical site (intracranial, intraspinal, intraocular,
retroperitoneal,
or pericardial).
In the ximelagatran
groups, on-treatment major bleeding events included GI bleeding in
9 patients (5 in the
36-mg group, 4 in the 24-mg group), with 2 events in the 36-mg group
reported as fatal
bleeding SAEs as noted above. Additional on-treatment major bleeding events
included 12 wound hematomas (7 in the 36-mg group, 5 in the 24-mg group) and 5
wound-bleeding events (all in the 36-mg group). Medical or surgical
intervention for the bleeding event was required in 14 ximelagatran-treated
patients (11 in the 36-mg group, 3 in the 24-mg group). These interventions
included evacuation/aspiration of clot or hematoma, incision and drainage,
wound irrigation and debridement, closure of wound, re-operation, endoscopy,
laparotomy and gastrostomy for ulcers and evacuation of subdural hematoma.
In the warfarin-treated
groups, on-treatment major bleeding events included GI bleeding in
3 patients and
haemarthroses in 2 patients. Additional on-treatment major bleeding events
included 5 wound
hematomas and 2 wound-bleeding events. Medical or surgical intervention for the
bleeding event was required in 6 warfarin-treated patients. The interventions included
evacuation/aspiration of blood or hematoma, surgical drainage, debridement of
wound haematoma, re-operation and removal of blood from knee, and transfusion.
1.5.1 Incidence of reported bleeding events
Fewer than 8% of
patients in each treatment group had a reported bleeding event during study
treatment. Two patients in the ximelagatran 36-mg group had fatal nonsurgical
bleeding events of GI hemorrhage.
In the 36-mg Pool, the
frequency of patients with a reported bleeding event was higher in the
ximelagatran group than in the warfarin group (7% and 5%, respectively).
Overall, the proportions of patients who had at least 1 reported bleeding event
were higher in the ximelagatran treatment groups (6.7% and 7.2% respectively)
than in the warfarin groups (5.0 and 5.6% respectively), as were the
proportions of patients who had an event that led to discontinuation of study
treatment (1.1% in ximelagatran group vs. 0.5% in warfarin groups). There was
no appreciable difference among groups with respect to SAEs of bleeding.
The overall frequencies
of on-treatment reported bleeding events for the 36-mg and 24-mg Pools are
shown in Table 11.
Table 11: Number (%) of patients who had an
on-treatment reported bleeding event in any category: Warfarin-comparison Pool
(exposed safety population)
The overall incidence of
adjudicated bleeding with ximelagatran was low and considered to be clinically
acceptable.
1.5.2 Conclusions on bleeding
A numerically higher
frequency of bleeding events was observed for ximelagatran in the oral
only, post-operative
program for TKR when compared with warfarin. The overall incidence of bleeding
with ximelagatran was low and considered to be clinically acceptable.
With respect to
on-treatment adjudicated events, major bleeding occurred in 0.9% of patients
treated with ximelagatran 36 mg, compared with 0.5% of patients treated with
warfarin. Major/minor bleeding occurred in 5.1% of patients treated with
ximelagatran 36 mg and 4.1% of patients treated with warfarin. Similar results
were observed for ximelagatran 24 mg bid compared with warfarin.
Fewer than 8% of
patients in any of the ximelagatran or warfarin groups had a reported bleeding
event during study treatment, and most events were non-serious. There was no
apparent relationship between ximelagatran dose and bleeding risk, as indicated
by similar proportions of patients with bleeding events (major and major/minor)
in the ximelagatran 36-mg and 24-mg groups in Study SH-TPO-0010.
Subgroup analyses of
major/minor bleeding events in the 36-mg and 24-mg comparison groups did not
reveal a subgroup with a clinically important difference in bleeding risk from
the entire population (ie, one which might require dose adjustment). In
general, treatment differences were consistent across subgroups.
1.6 Analysis of ALAT elevations in the Surgical
population
Since ALAT is a more
specific marker of liver cell damage than ASAT, and because there was no
pattern for an increase in alkaline phosphatase (ALP) or bilirubin in
isolation, ALAT forms the basis of the analysis. A threshold of >3x ULN ALAT
was used to indicate a signal of potential clinical relevance.
1.6.1 Studies EXULT A (SH-TPO-0010) and EXULT B
(SH-TPO-0012)
Changes from baseline in
clinical chemistry parameters, including elevations in ALAT,
reflected surgical
intervention and postoperative recovery and were generally comparable in
the ximelagatran and
warfarin treatment groups. These changes generally occurred during the
immediate postoperative course of treatment and at the time of the end of
treatment with a return to near baseline levels at follow-up.
In EXULT A, there were
no differences between the ximelagatran groups and the warfarin
group for patients who
had ALAT elevation >3x ULN at the end of treatment (6/723, 36-mg;
4/706, 24-mg; 12/704
warfarin). During the follow-up period, 4 patients in the ximelagatran
36-mg group, 1 patient
in the ximelagatran 24-mg group, and 0 in the warfarin group had their
first ALAT elevation
>3x ULN. Three of the 4 patients in the ximelagatran 36-mg group had their
first ALAT elevation >30 days after receiving their last ximelagatran dose
while the fourth patient had their first ALAT elevation 28 days after receiving
their last ximelagatran dose.
In EXULT B, there were
no differences between the ximelagatran and warfarin groups for
patients who had ALAT
elevations >3x ULN at end of treatment (7/1095, ximelagatran 36-mg
group; 6/1087 warfarin
group). During the follow-up period, 4 additional patients had their
first ALAT elevation
>3x ULN: 3 in the ximelagatran 36-mg group and 1 in the warfarin
group. For all 3
ximelagatran 36 mg patients, the elevations were resolved within 30 days of elevation, including one patient
(SH-TPO-0012-510-14309) who began a LMWH on postoperative day 11 as treatment
for DVT.
Drug effects on liver
toxicity beyond 4-6 weeks are unknown. It should be noted that elevation of
hepatic enzymes was typically seen between 2nd and 6th
month after starting ximelagatran (long-term exposure data).
1.6.2 Hepatobiliary AEs in the Surgical
population Warfarin-comparison Pool
Overall frequency of AEs
in the liver and biliary system disorder was slightly higher in
the ximelagatran 36-mg
(EXULT) group compared to warfarin (6.7% vs 5.4%) and in the
ximelagatran 24-mg
group, 5.5% ximelagatran 24-mg versus 5.1% warfarin. This was due to a higher
rate of reported GGT increased (ximelagatran: 5.6% in the 36-mg group, 4.4% in
the 24-mg group, versus 4.2% in both warfarin groups).
Incidences of ALAT
(SGOT) increased reported as AEs were similar across the groups (36-mg
ximelagatran comparison: 2.1% ximelagatran 36-mg, 1.3% warfarin; 24-mg
comparison group: 1.4% ximelagatran 24-mg, 1.5% warfarin). There were no
hepatobiliary fatal SAEs, non-fatal SAEs or DAEs in either ximelagatran group.
1.6.3 Conclusions of hepatobiliary effects in the
Surgical population
There were no
differences in the on-treatment incidences of ALAT elevation between
ximelagatran and warfarin. However, during the follow-up period (4-6 weeks), 7
patients in the ximelagatran group, and 1 in the warfarin group had their first
ALAT elevation >3x ULN. Drug effects on liver toxicity beyond 4-6 weeks are
unknown. It should be noted that elevation of hepatic enzymes was typically
seen between 2nd and 6th month after starting
ximelagatran (long-term exposure data).
1.7 Coronary artery disease adverse events
Serious adverse events
on coronary artery disease including MI are summarized in table 12.
Table 12: Summary of CAD adverse events following short-term use
of ximelagatram#
|
|
Exult A
|
|
Exult B##
|
|
Exult A and B
|
|
|
Event: N (%)
|
Exanta
N=1526
|
Warfarin
N=759
|
Exanta
N=1151
|
Warfarin
N=1148
|
Exanta
N=2677
|
Warfarin
N=1907
|
|
MI
|
11 (0.72)
|
1
(0.13)
|
5
(0.43)
|
3
(0.26)
|
16*
(0.60)
|
4*
(0.21)
|
|
Other
CAD (Angina/ischemia)
|
3
(0.2)
|
0
|
1
(0.17)
|
1
(0.09)
|
4
(0.15)
|
1
(0.05)
|
|
Total
|
14
(0.92)
|
1
(0.13)
|
6
(0.7)
|
4
(0.35)
|
20**
(0.75)
|
5**
(0.26)
|
|
|
|
|
|
|
|
|
|
|
*p=0.04951; **
p=0.02800
#Excluded 4 patients who did not
take study medications, 3 in ximelagatran group (ID: #3206, #7086 and #10944)
and 1 in warfarin group (ID: #9089) whose death was also adjudicated by the
central adjudication committee as PE.
##one case of sudden death
(#15016) in the warfarin group was included as MI and two cases of sudden
deaths in the Exanta group (ID: #14366 and 12122) were excluded from the
analysis.
Summarized
from Module 5, vol. 1 Table 54 and vol. 2 Table 11.3.5.1; vol. 3 Table 55 and
vol. 4 Table 11.3.5.1
In both Exult A and
Exult B, the proportion of patients with coronary artery disease adverse events
(MI and angina) was higher in the ximelagatran groups than in the warfarin
groups. After combining Exult A and Exult B, proportion of patients with
coronary artery disease adverse events was statistically significantly higher
in the ximelagatran group (20/2677, 0.75%) than in the warfarin group (5/1907,
0.26%) in the TKR population (p=0.02800). Proportion of patients with MI was
also higher in the ximelagatran group (16/2677, 0.60%) than in the warfarin
group (4/1907, 0.21%) in the TKR population (p=0.04951). There were no
appreciable differences between the treatment groups for underlying diseases
including hypertension, diabetes mellitus, hypercholesterolemia, coronary
atherosclerosis, as well as age, gender and weight (Table 13).
Table 13: Concomitant medical conditions in
studies EXULT A and B
___________________________________________________________
Ximelagatran Warfarin
N=2225 N=1575
n
(%) n (%)
___________________________________________________________
Hypertension
1325 (59.6) 963 (61.1)
hypercholesterolemia 339
(15.2) 243 (15.4)
Diabetes mellitus 290
(13.0) 199 (12.6)
Coronary atherosclerosis 155
(6.9) 99 (6.3)
____________________________________________________________
N=2677 N=1907
Gender Male 1015 (37.9) 715 (37.5)
Age, years Mean (SD) 67.7 (9.5) 67.5 (9.5)
Weight (kg) Mean (SD) 84.3
(18.1) 84.5 (17.7)
____________________________________________________________
All of events occurred
during the first 2 weeks, except 2 cases of MI in the ximelagatran group that
occurred at day 28 and day 39, and 1 case in the warfarin group reported at day
21. In the ximelagatran group, 14 cases occurred during the treatment period; 3
cases occurred 1-4 days after last dose of ximelagatran; 2 cases, beyond 1 week
after last dose. The relationship between last dose and events in 1 other case
is unclear. The diagnoses of MI in 1 patient in the warfarin group is unclear
(PE can not be ruled out). One case was reported at day 21. Four other cases
were reported during the treatment period.
Considering ximelagatran as an anticoagulant with potential to treat MI,
these results are worrisome.
2: The non-surgical
population who received study drug for > 35 days
are presented for the LTE pool in Table 14.
Table 14:
Number (%) of patients who had an adverse event: LTE pool
The overall proportion of patients reporting adverse events
was high (85%) due to the severity of the underlying diseases in these
populations but there was no difference between the treatment groups. The
frequency of SAEs (fatal and non-fatal) was similar between the treatment
groups. The proportion of patients who discontinued study drug was higher in
the ximelagatran group (17.2%) than in the comparator group (12.9%). This was
mostly due to discontinuation of study drug due to elevation of hepatic
function tests. The
most commonly reported AEs in the LTE pool are presented in Table 15. Adverse
events reported with a frequency of at least 4.0% in any column are presented.
The events are sorted by the ximelagatran column.
Table 15: Number (%)
of patients with the most commonly reported AEs: LTE pool
2.2 Deaths
The overall mortality in the ITT population was 3.9% in the
ximelagatran group and 4.4% in
the comparator group. AEs that most frequently led to death
were myocardial infarction,
sudden death, cardiac arrest and cardiac failure, events
expected for the 2 populations at risk
of cardiovascular events, AF and post ACS.
2.2.1
Deaths: LTE pool
Death was included in the definition of the endpoints in the
studies in the LTE pool and all
cause mortality is analyzed using the ITT population.
Overall mortality was similar between ximelagatran and comparators.
Table 16: Risk of
death in the LTE pool, estimated relative risk with 95% CI (ITT population)
Because the comparator
was placebo in the VTE-P and Post ACS pools, a higher mortality
might have been expected
for the comparator group. Therefore, the overall mortality has also
been compared between
ximelagatran and the active comparator (warfarin). Overall mortality was
similar between ximelagatran (6.5%) and warfarin (7.1%).
2.2.2
Fatal SAEs in the safety population
There were 224 fatal cases during active treatment, 112 in
the ximelagatran treatment groups and 112 in the comparator groups. A further
331 patients died after stopping study drug (166 in the ximelagatran group and
165 in the comparator group).
The most common fatal SAE was myocardial infarction (MI).
During active treatment, the proportion of patients who died due to acute MI
was the same for the 2 treatment groups (0.2%). However, after stopping
treatment fatal acute MIs occurred more frequently in the ximelagatran group
(0.4%) than the comparator group (0.2%).
In the post ACS pool, there was an increased proportion of
fatal myocardial infarctions in the post-treatment period (1.1% vs 0.5%). There
were 29 fatal cases during active treatment, 15 (1.2%) in the ximelagatran
treatment groups and 14 (2.2%) in the placebo group. A further 35 patients died
after stopping study drug, 27 (2.2%) in the ximelagatran groups and 8 (1.3%) in
the placebo group. All deaths during treatment were reported in terms
associated with cardiovascular
disease, with the exception of one suicide in the placebo
group.
2.2.3
Fatal SAEs considered causally related by the investigator: LTE pool
There were no differences between treatments concerning the
number of fatal SAEs considered by the investigators to be causally related to
study drug (Table 17).
Table 17: Number (%)
of patients with fatal serious adverse event considered causally related by the
investigator: LTE pool
|
During the treatment
After treatment
ximelagatran
Comparators ximelagatran Comparators
n=6931 n=6216
n=6819 n=6104
|
|
Total 14 (0.2) 10 (0.2) 5 (0.1)
8 (0.1)
GI haemorrhage 1
1
Haematemesis 1
1
Hepatitis infectious
1
Myocardial infarction 1
Cardiac arrest 1 2
Cardio-respiratory arrest 1
Fibrillation ventricular 1
Cerebral haemorrhage 2 2 1 2
Cerebrovascular disorder 1 1 2
Haemorrhage intracranial 1 1
Subarachnoid haemorrhage 1
Aspiration pneumonia 1
Bronchitis aggravated
1
Hypoxia
1
Resp distress syndrome adult
1
Respiratory disorder 1
Retroperitoneal haemorrhage
1
Myeloid metaplasia
2
Pulmonary carcinoma 1
Sudden death 3 1
Sepsis 1
|
2.2.4
Comparison of deaths between pools
There was a similar mortality rate in patients taking
ximelagatran and those taking comparators in all pools. The most frequent AEs leading to death were
driven by the 2 populations at risk of cardiovascular events, AF and post ACS:
myocardial infarction, sudden death, cardiac arrest, cardiac failure. There were no obvious differences in the
rates of such fatal cardiac events between groups, except for an excess of
myocardial infarctions in patients who had discontinued ximelagatran and this
was seen in the post ACS pool. Most of
these AMIs started during treatment.
2.3 Serious adverse events other than death
There was a higher frequency of SAEs in the hepatobiliary in
the ximelagatran groups relative to comparator treatment in all pools.
A higher frequency of SAEs related to coronary artery
disease was seen in the ximelagatran groups in all pools with the exception of
the Post ACS pool.
Subjects in the safety population who experienced non-fatal
SAEs during or after active study treatment are included in the following
tables.
Table 18 Number (%) of patients with the most
commonly reported non-fatal serious adverse events: LTE pool
A total of 26.3% of patients in the ximelagatran group and
27.1% of patients in the comparator group experienced a non-fatal SAE during
treatment. A further 5.5% of patients in
the ximelagatran group and 4.3% of patients in the comparator group experienced
a non-fatal SAE after stopping study drug.
The most common non-fatal SAEs were cardiovascular events
which reflect the diseases under study. The most common non-fatal SAEs
considered to be causally related to ximelagatran were increases in hepatic
enzymes.
The profile of the non-fatal SAEs was consistent with the
pattern of all AEs in the pool. There was a higher reporting frequency of SAEs
in the hepatobiliary organ system in the ximelagatran groups compared to
warfarin or placebo in all pools.
A higher frequency of SAEs related to coronary artery
disease was seen in the ximelagatran groups in all pools with the exception of
the Post ACS pool.
2.4 Discontinuation
of Study Drug due to an Adverse Event (DAE)
The most common AEs causing discontinuation of study drug
for the LTE pool are presented in Table 19.
Table 19: Number (%) of patients with the most commonly
reported DAEs: LTE pool
The proportion of patients who discontinued study drug was
higher in the ximelagatran group (17.2%) than in the comparator group (12.9%). This was mostly due to the discontinuation of
study drug due to increased liver function tests (LFTs).
Apart from increases in hepatic enzymes, the most frequent
reasons for discontinuations were related to coronary artery disorder in the
ximelagatran group (0.6% vs. 0.3%). Thromboembolic events were more common DAEs
in the comparators group (1.3% vs. 0.4%), because of placebo control in
secondary prevention study.
Other common causes of discontinuations included bleeding
events, with no difference between ximelagatran and the comparators, except for
hematuria and rectal haemorrhage/melaena, which caused slightly more
discontinuations in the ximelagatran group than in the comparators group.
2.5 Bleeding Events
2.5.1 Major bleeding events
The risk of a major bleeding event is summarized by
treatment group in Table 20.
Table 20: Risk of a
major bleeding event per patient year
In patients with AF, ximelagatran 36 mg was associated with
statistically significantly fewer major bleeding events than warfarin (AF pool;
2.4% and 3.4% for the ximelagatran and warfarin group, respectively,
p=0.0288). However, there were no
significant differences for major bleeding events between the groups in each of
2 pivotal studies (SH-TPA-0003 and STP-0005). In patients with acute VTE,
ximelagatran 36 mg (1.1%, 14/1240) was associated with numerically fewer major
bleeding events than enoxaparin/warfarin (2.1%, 26/1249).
In patients undergoing extended secondary prophylaxis for
VTE, ximelagatran 24 mg was associated with a similar incidence of major
bleeding events to placebo (1% and 0.8%, respectively).
2.5.2 Major/minor bleeding events
The risk of a major/minor bleeding event is summarized by
treatment group in Table 21.
Table 21: Risk
of a major/minor bleeding event per patient year
In patients with AF, ximelagatran 36 mg was associated with statistically
significantly fewer major/minor bleeding events than warfarin (AF pool; 32.0% and 39.1% for the
ximelagatran and warfarin groups, respectively, p<0.0001). In patients with acute VTE, ximelagatran 36
mg was associated with numerically fewer major/minor bleeding events than
enoxaparin/warfarin (5.5% vs. 7.0%).
In patients undergoing extended secondary prophylaxis for
VTE, ximelagatran 24 mg was associated with a numerically more major/minor
bleeding events than placebo (21.9% and 18.2% for the ximelagatran and the
placebo group, respectively).
In the dose-finding study in post ACS patients, the risk of
a major/minor bleeding event with ximelagatran plus ASA increased with
increasing dose. Patients who received
ximelagatran plus ASA had statistically significantly more major/minor bleeding
events than patients who received placebo plus ASA (pooled doses; 19.8% and 11.3% for the ximelagatran plus
ASA, and the placebo plus ASA, respectively, p<0.0001).
2.5.3
Fatal bleeding events
The incidence of fatal bleeding events (adjudicated fatal
events, and bleeding-related serious
adverse events leading to death) is summarized by treatment
group in Table 22.
Table 22: Summary of
fatal bleeding events, by study
OT: on treatment
In addition to the 13 patients with bleeding-related serious
adverse events leading to death whilst on treatment in Table 20 (safety
population), a further 16 patients had bleeding-related serious adverse events
leading to death after stopping treatment.
Of these 16 patients, 7 had received ximelagatran and 9 had received
warfarin. Thus in total, 29 patients
experienced bleeding-related SAEs with a fatal outcome.
Almost all fatal bleeding events were intracranial (17
cases) or gastrointestinal (10 cases), except 1 case of pericardial and 1 case
of retroperitoneal bleeding.
Of the 29 patients who experienced bleeding-related SAEs
with a fatal outcome, 13 were not included in the “on treatment” analysis of
bleeding outcomes. Ten events were
intracerebral haemorrhages that were adjudicated as strokes by the adjudication
committee.
Patient SH-TPV-0002-701-4723 was not included in the
OT-analysis as a fatal bleed. This
patient had a “Bleeding per rectum” that started 30 days after last study drug
intake and therefore the adjudication committee classified this as "Death
not associated with VTE or bleeding".
Conversely, 7 patients in the ximelagatran group and 2 patients
in the warfarin group who had a fatal major bleed according to the adjudication
committee are not included in the 29 patients who experienced bleeding-related
SAEs with a fatal outcome. Eight
patients were not captured by the search on bleeding terms because the term
used by the investigator to describe the AE leading to death did not match the
preferred terms used to identify patients with bleeding events. The remaining
patient (SH-TPA-0003-316-2826) in the ximelagatran group died after discontinuing
study drug and is therefore not shown in the AE tables.
In summary, a total of 38 patients experienced
bleeding-related SAEs with a fatal outcome, 19 cases in each treatment group
(ximelagatran or comparator).
2.5.4 Overview of
reported bleeding-related adverse events across indication pools
An overview of the incidence of bleeding adverse events is
summarized by treatment for the individual pools in Table 23.
Table 23:
Number (%) of patients who had bleeding-related adverse events
In patients with AF, the incidence of reported bleeding
adverse events with ximelagatran 36 mg (32.6%) was less than that observed with
warfarin (40.1%). The incidence of
serious adverse events and discontinuations due to a bleeding adverse event was
low and similar in both treatment groups.
In patients with acute VTE, the incidence of reported bleeding adverse
events with ximelagatran 36 mg (18.3%) was less than that observed with
enoxaparin/warfarin (25.4%). The
incidence of serious adverse events and discontinuations due to a bleeding
adverse event was low and similar in both treatment groups.
In patients undergoing extended secondary prophylaxis for VTE, the
incidence of reported bleeding adverse events with ximelagatran 24 mg was
numerically greater than that observed with placebo. The incidence of serious adverse events and
discontinuations due to a bleeding adverse event was low and similar in both
treatment groups.
The incidence of
reported bleeding adverse events in patients receiving ximelagatran and ASA
(20.1%) was higher than that observed with placebo and ASA (11.4%). The incidence of serious adverse events and
discontinuations due to a bleeding adverse event with ximelagatran plus ASA was
low (2.7% and 4.5% for serious adverse events and discontinuations due to
adverse events, respectively), but higher than that observed with placebo and
ASA (1.1% and 0.9% for serious adverse events and discontinuations due to
adverse events, respectively).
In AF patients, the most
commonly reported bleeding related AEs for ximelagatran-treated patients were
purpura (which was the preferred term used to code unspecified hematomas,
bruises and petechiae) (11.1%), epistaxis (7.2%), haematuria (5.4%) and rectal
haemorrhage (2.9%).
In patients with an
acute VTE, the most commonly reported bleeding related AEs for
ximelagatran-treated patients were purpura (4.6%), epistaxis (3.2%), haematuria
(2.8%) and gingival bleeding (2.0%).
In patients undergoing
extended secondary prophylaxis for VTE the most commonly reported bleeding
related AEs for ximelagatran-treated patients were haematuria (6.0%), purpura
(4.7%), melaena (3.6%), and rectal haemorrhage (1.6%).
The most commonly
reported bleeding AEs in patients receiving ximelagatran and ASA were epistaxis
(4.9%), haematuria (4.9%), melaena (3.7%) and purpura (3.6%).
2.5.5 Relationship between exposure to melagatran and bleeding events
The association between
AUC and the cumulative risk of a major/minor bleeding event is summarized for
ximelagatran-treated patients in the AF pool in Table 24.
Table 24:
Association between AUC and cumulative risk of having a bleeding event
(major or minor) after one year in the study
The risk of having a
major/minor bleeding event with ximelagatran 36 mg increases with increasing
AUC values (hazard ratio 1.17, 95% CI: 1.12, 1.21)
There was no
statistically significant relationship between the risk of having a major/minor
bleeding event with ximelagatran 24 mg and increasing AUC values (hazard ratio
1.08, 95% 0.90, 1.29).
2.5.6 Subgroup analyses of bleeding events:
Within-treatment group
comparisons suggested that, for both ximelagatran and warfarin, patients >75
years old, and those with prior stroke/TIA, were at an increased risk of
major/minor bleeding. In the
ximelagatran group only, CrCL <80 mL/min, previous CAD and diabetes mellitus
were also suggested to be associated with an increased risk of major/minor
bleeding events. In the warfarin group,
the same conclusion was suggested for patients with paroxysmal AF and those who
had previously taken aspirin.
For the majority of
subgroups investigated, patients were statistically significantly less likely
to have a major/minor bleed with ximelagatran 36 mg than warfarin. Two significant treatment by risk factor
interactions were detected, for CrCL <80 mL/min (p<0.001) and diabetes
mellitus (p=0.002). In terms of the key
demographic characteristics, the following subgroups were statistically
significantly less likely to have a major bleed with ximelagatran 36 mg than
warfarin patients with a CrCL >80 mL/min, patients less than 75 years
old, patients with a BMI >25, males and females, patients with a
weight >50 kg and Caucasians.
There were no subgroups
that were statistically significantly less likely to have a major/minor bleed
with warfarin compared to ximelagatran.
2.6 Hepatobiliary effects
It should be noted that
the following patients have been excluded from the studies:
·
Patients
with known clinically significant liver disease (as judged by the investigator)
or persistent ASAT and/or ALAT > 3 x ULN (defined by central laboratory)
·
Patients
with continuous treatment with NSAID or Known drug addiction and/or alcohol
abuse
at least monthly for the
first 6 months and if ALAT increased to >3xULN, were monitored
weekly; if ALAT reached
>7xULN study drug was stopped. From 2 November 2001, this
algorithm was changed.
The threshold for beginning weekly monitoring was reduced from
3xULN to 2xULN and the
threshold for discontinuation of study drug was revised from
7xULN to 5xULN (or
persistent increase >3xULN for up to 4-8 weeks). In the program,
40% of the
ximelagatran-treated patients who had an ALAT >3xULN were monitored using
the more stringent
algorithm.
2.6.1 Patients contributing to ALAT measurement
The number of randomized
patients contributing to ALAT testing is shown in Table 25.
Table 25: Number of patients randomized, and
contributing ALAT measurements over time in the long-term studies (ITT
population) - Central laboratory data only
Of the 6948 patients
randomized to ximelagatran, 6840 contributed at least one ALAT measurement and
5528 had an ALAT measurement at the 6-month visit.
2.6.2
Elevations in liver function tests (LFTs)
The distribution of patients with elevated ALAT, ASAT, ALP
and total bilirubin, according to
various multiples of ULN is shown for the LTE pool in Table
26 (Central laboratory data
only).
Table 26: Cumulative
incidence of patients with elevated ALAT, bilirubin, ASAT, G-GT and ALP (ITT
population): LTE pool - Central laboratory data only
The pooled data shows a similar pattern to that seen in the
individual studies. ALAT showed a significant increase in ximelagatran-treated
patients compared to those treated with comparators at all thresholds. ASAT
increased in conjunction with ALAT. There was no similar increase for
ximelagatran relative to comparators in total bilirubin and ALP.
ALAT is the main marker of a hepatic effect in the
ximelagatran group compared to the comparator. There is a strong correlation
with ASAT, but ALAT is generally higher and is known to be more specific to the
liver. The elevation in the other tests is not as different between groups, and
there is no correlation between ALAT and ALP or bilirubin. These features point
to a predominantly hepatocellular type of hepatic injury, as opposed to a
cholestatic type.
As ALAT is a more specific marker of liver cell damage than
ASAT, and there was no pattern
for an increase in ALP or bilirubin in isolation, ALAT was
used for monitoring and management decisions and forms the basis of the
analysis. A threshold of >3xULN ALAT is generally considered to represent a
clinically significant elevation. Lower cut-off levels are considered to be
less informative due to the commonness of slight elevations in untreated
populations. Therefore, ALAT values of >3xULN have been used to indicate a
signal of potential clinical relevance.
2.6.3 ALAT
elevation according to various thresholds
The figure shows the
number of patients presenting with ALAT >3xULN for the first time and it
should be noted that there were 6948 patients in the ximelagatran group and
6230 in the comparator group. In the
first month of treatment there was no difference in the incidence of ALAT
>3xULN between ximelagatran (23 cases) and comparator-treated patients (25
cases). The difference became
significant at 2 months. Of the 531
ximelagatran-treated patients who had ALAT >3xULN, 495 (93.0%) were detected
during the first 6 months and 519 (97.7%) were detected within the first 12
months. Beyond 12 months, few new patients
presented with ALAT >3xULN.
Regardless of the
magnitude of the ALAT increase examined, the time pattern was consistent. In
the ximelagatran group, the majority of patients who experienced an elevation
in ALAT presented between 2 and 4 months. Beyond 12 months the incidence of
increased ALAT was similar to the comparators.
2.6.6 Recovery of elevated ALAT values towards normal
Among
the 531 patients in the ximelagatran group who presented with an ALAT
>3xULN, 206 (39%) completed the study on study drug. The remaining 325 patients (61%) discontinued
study drug prematurely. The
analysis of the reduction of elevated ALAT toward normal is presented in Table
30.
Table 30
Number of ximelagatran-treated patients with ALAT>3xULN, measured at
the Central laboratory by magnitude of last recorded ALAT measurement (ITT
population): LTE pool
This table includes
ximelagatran-treated patients who had an ALAT >3xULN recorded at the Central
laboratory during the studies categorized by their maximal ALAT elevation
(>3, >5 or >10xULN). For each
category, the number of patients who had a last recorded ALAT value of <1,
<2, <3 or >3xULN, is shown. The
table is further subdivided into those patients who continued on study drug and
those who stopped study drug. For
example, from the second column of the table it can be seen that 84 patients
who had a maximal ALAT elevation of >3xULN but <5xULN, had returned to an
ALAT <1xULN at their last recorded measurement, while continuing to
take study drug. From the penultimate
column in the table it can be seen that 8 patients who had a maximal ALAT
elevation of >10xULN, still had ALAT >3xULN at their last recorded
measurement, having stopped taking study drug.
Of the 531
ximelagatran-treated patients who had an ALAT elevation >3xULN recorded by
the central laboratory, 502 (95%) had their ALAT return to <2xULN by the
last measurement taken before the cut-off for this file. So far, it is not possible to identify who
the patients are that will not return to baseline. The mean number of days
taken for ALAT to return to <2xULN was similar whether the patients
continued to take ximelagatran or not (Table 31).
Table 31
Mean number of days between first ALAT elevation >3xULN (measured at
the Central laboratory) to normalization for ximelagatran-treated patients (ITT
population): LTE pool
Most cases show a peak
of ALAT within the first 2 to 3 months post-randomization and a decline back
towards baseline within about 6 months post-randomization.
The pattern of return to
baseline or ULN was similar whether the patient discontinued study drug or not,
and only sustained above ULN in a few cases.
A total of 35 patients,
30 in the ximelagatran group and 5 in the comparator group, still had ALAT
>2xULN at the last measurement (including local laboratory measurements). Of
the 30 ximelagatran-treated patients, 11 died while their ALAT was still
elevated; 3 patients had an alternative explanation for the raised LFTs
(alcohol); 2 patients were lost to follow-up and one patient had a final ALAT
measurement that according to the investigator had “decreased to a medically
insignificant level”. The remaining 13
patients continued under surveillance at the time of the cut-off for this
file.
2.6.7 Re-challenge to ximelagatran after
temporary discontinuation of study drug with ALAT elevations
Eighteen patients who
discontinued study drug with elevations of ALAT subsequently resumed treatment
after ALAT had returned to the normal range. Of these 18 patients, 2 (Patient SH-TPA-0003-017-2619
and Patient SH-TPA-0005-370-5718) again experienced elevations of ALAT after
drug was resumed.
2.6.8 Elevated ALAT by dose
Table 32 shows the
cumulative incidence of ximelagatran-treated patients with elevated ALAT by
dose in study SH-TPC-0001.
Table 32
Cumulative incidence of ximelagatran-treated patients with elevated ALAT
by dose in study SH-TPC-0001 (ITT population)
There was not a marked
dose response over the dose range 24 mg to 60 mg but there was a noticeably lower
incidence of all multiples of ULN at the 24 mg dose compared to the higher
doses.
2.6.9 Combination of ALAT and bilirubin elevation
The combination of
transaminase and bilirubin elevation has been considered to predict the
occurrence of severe injury in some patients.
The number of patients in each of the studies that contribute to the LTE
pool who had an increase in total bilirubin >2xULN within one month
following an increase in ALAT >3xULN are shown in Table 33.
Table 33
Concomitant elevations of ALAT >3xULN and bilirubin >2xULN (ITT
population) - Central laboratory data only
ALAT >3xULN was
associated with bilirubin >2xULN (within one month following the rise in
ALAT) in 0.4% (26/6948) of all patients who were exposed to ximelagatran >35
days as compared to 0.1% (4/6230) of patients exposed to comparators.
Additional ALAT and
bilirubin data were obtained from tests performed at local laboratories. These
included 11 new cases (10 ximelagatran, 1 comparator) who had an increase in bilirubin
>2xULN within one month following an increased ALAT >3xULN. One additional patient (#7859) described in
the section of Deaths in ximelagatran-treated patients with ALAT >3xULN (see
below) had bilirubin elevation >
5.6x ULN. This patient was not included in the sponsor’s analysis for
combination elevation. Therefore, at
the cut-off date for this file there were 37 such cases in the ximelagatran
group and 5 in the comparator group (0.53% vs 0.08%). The ximelagatran-treated patients who had an
increase in total bilirubin >2xULN within one month following an increase in
ALAT >3xULN are summarized in Tables below.
Table 34
List of ximelagatran-treated patients with concomitant elevations of
ALAT >3xULN and bilirubin >2xULN – Central laboratory data only
Table 35
List of ximelagatran-treated patients with concomitant ALAT >3xULN
and bilirubin >2xULN – local laboratory data only
Table 36
List of ximelagatran-treated patients with concomitant ALAT >3xULN
and bilirubin >2xULN – local laboratory data only
Concomitant elevations
of ALAT >3xULN and bilirubin
>2xULN were observed during the first month of ximelagatran therapy in 6 of
37 patients.
Two comparator-treated
patients with concomitant ALAT >3xULN and bilirubin >2xULN died and both
died from pancreatic cancer.
Nine
ximelagatran-treated patients who died are presented here more in detail
(including patient # 7859 who was missed by the sponsor for concomitant ALAT
and bilirubin elevation analysis).
·
Patient
7259, an 80 year old male, began ximelagatran 36 mg bid treatment on 11 June
2001. He experienced elevated liver transaminases with biopsy-demonstrated
hepatic necrosis and a fatal bleed due to a duodenal ulcer. The patient had a
medical history of hyperlipidemia treated in the past with simvastatin until
March 1999, AF since 1996, hydronephrosis probably related to an ectopic ureter
insertion, urinary retention, fibromyalgia treated with prednisone in the past,
coronary artery disease treated with bypass grafting in 1999, and right colon
cancer diagnosed in 1999. Concomitant medications included Lopressor
(metoprolol), digoxin, and Flomax (tamsulosin). On 30 May 2001, the patient's
baseline liver function tests were normal with ALAT 16 U/L, ASAT 22 U/L, ALP 67
U/L and total bilirubin 0.9 mg/dL . On 6 August 2001, at the Month 2 Visit, his
LFTs were mildly elevated, but less than the 3x ULN threshold that required
discontinuation of study medication . At the next scheduled visit (4 September
2001) the transaminases were found to be further elevated (ALAT 970 U/L, ASAT
698 U/L, ALP 142 U/L), leading to weekly LFT monitoring and study drug
discontinuation on 7 September 2001. Transaminases continued to increase. On 19
September 2001, ALAT and ASAT were 1502 U/L and 1355 U/L, respectively; ALP was
154 U/L; total bilirubin was 2.4 mg/dL (nearly twice the ULN) and direct
bilirubin was 0.6 mg/dL. Serologies for hepatitis A, B, and C, cytomegalovirus,
Epstein-Barr, and herpes simplex viruses did not show a recent viral infection.
Carcino-embryonic antigen and antinuclear antibodies were negative. Abdominal
ultrasound showed normal liver, normal gallbladder, normal biliary tree and 2
simple cysts in the right kidney. An abdominal and pelvic CT scan performed on
21 September 2001 showed no significant new findings compared to a prior
examination (3 August 2000). Liver transaminases peaked on 27 September 2001
and then decreased on 4 October 2001. ALP peaked at 198 U/L on 3 October 2001
and decreased to 170 U/L on 4 October 2001. Total bilirubin was 10.7 mg/dL on 3
October 2001 and then decreased to 7.9 mg/dL on 4 October 2001. Prothrombin
time (13.6 sec) and INR (1.2), which were close to normal on hospital admission
(20 September 2001) started to increase on 1 October 2001, reaching16.3 sec and
1.7 respectively. Conversely, albumin decreased to 2.9 g/dL on 2 October 2001.
This laboratory profile suggested impairment of his synthetic liver function. A
liver biopsy performed on (27 September 2001) demonstrated "severe active
hepatitis with hepatocyte necrosis, areas of collapse and marked bile ductular
proliferation consistent with acute submassive necrosis." The hepatologist
considered the most likely explanation was medication-induced hepatitis. INR
remained elevated (1.8 on 8 October 2001) and serum albumin low (2.5 g/dL on 8
October 2001). platelet count was 65,000/mm3 (29 October 2001).
Profound fatigue continued with no evidence of encephalopathy. However, he had
developed ascites, significant lower extremity edema and oliguria. On the
morning of 3 November 2001, the patient's wife found him unresponsive at home.
Resuscitation failed and the patient was pronounced dead. The cause of death
was upper GI bleed due to duodenal ulcer. An autopsy confirmed the presence of
atherosclerotic disease, ischemic heart disease with triple CABG and atrial
septal defect repair; adenocarcinoma of the colon resected with no evidence of
recurrence or metastatic disease, and left hydronephrosis with no evidence of
mechanical obstruction. The significant findings were: A large duodenal ulcer
(2.5 cm) with erosion into pancreas and peripancreatic soft tissue and
hemorrhagic contents through most of the small intestine with intact bowel. A
small, friable and diffusely mottled liver suggestive of severe diffuse hepatic
necrosis. Microscopically, there was extensive liver necrosis with hepatocyte
dropout and bile duct proliferation, similar to that seen in the previous
biopsy. A significant amount of hepatic parenchyma remained. Tissue
architecture showed early resolution of the inflammation compared to the
previous biopsy. There was serous ascites in the abdomen. The spleen was not
enlarged. Moderate reduction of megakaryocytes in bone marrow. The cause of
death was an acute gastrointestinal bleed from a duodenal ulcer, with a
coagulopathic state from hepatic injury contributing to death. Both decreased
clotting factors and platelet reduction cause the coagulopathy, the latter
related to a decreased number of megakaryocytes in the bone marrow. The autopsy
report speculated that prednisone therapy may have caused the duodenal ulcer
and decreased synthesis of thrombopoietin by the liver could have played a role
in the thrombocytopenia. The investigator assessed the event of liver failure
as being related and the event of fatal bleed due to duodenal ulcer as not
related to the study medication.
·
Patient 5442
was a 73 year old male Caucasian. Relevant medical history included diabetes
mellitus, systemic lupus erythematosus, hypertension, heart disease, gastric
ulcer, COPD and cardiac arrhythmia. The reason for entering the study was DVT.
The patient received 36 mg Ximelagatran b.i.d. Transaminases were slightly
increased (ASAT 60 U/l; ALAT 60 U/l; AP 210 U/l), nine days after start of
study medication, but this was thought to be due to the known lupus
erythematosus which was otherwise not active (titer of antinuclear antibodies
> 1:80, i.e. normal). Eighteen days after commencing study medication, the
patient experienced hepatitis type B and was hospitalized. Hepatitis serology
had been done six days before admission because of rising transaminases and
showed HBs antigen, HBc antibody and HBe antigen 2 positive, while HBs
antibodies, hepatitis C virus antibodies, HBe antibodies, HAV-Ak-IgM and
HBc-Ak-IgM were all negative. From this constellation with absence of
antibodies an acute hepatitis B was diagnosed. With regard to the normal
incubation time, infection had probably occurred before inclusion into the
study, but a plausible source of infection could not be detected. Transaminases
continued to rise. Four days after hospitalization, ASAT was 354 U/l, ALAT 367
U/l, AP 292 U/l and G-GT 54 U/l. LDH had increased to 360 U/l and bilirubin was
1.8 mg/dl. Two days later study medication was withdrawn. The patient's general
condition was good, without signs of hepatic encephalopathy or failure. Two
days after withdrawal of study medication, ASAT was 593 U/l, ALAT 518 U/l and
bilirubin 4 mg/dl. The next day the patient was transferred to an infection
treatment unit. The patient began to develop icterus and bilirubin tests taken
ten days, 15 days and 19 days after onset, showed a rapid increase to 8 mg/dl,
17.2 mg/dl and 26.8 mg/dl, respectively. Transaminases meanwhile decreased
slightly. Eleven days after onset of the event, the patient complained of
nausea and pain in his right flank. Five days later, a gastroscopy performed
showed multiple gastric ulcers covered with fibrin, but no signs of acute
bleeding. Quick value, which had been around 40% before, dropped to 29 % with
an international normalized ratio of 2.3. ASAT value was 287 U/l and ALAT was
189 U/l approximately three weeks after onset. Therapy consisted of low
molecular heparin, oral iron substitution, pantoprazole, metoclopramide,
lactulose, prednisolone, amino acid infusions and amoxicilline + clavulanic
acid. The patient's general condition deteriorated. Abdominal computerized
tomography performed 18 days after onset, showed beginning formation of
ascites. On that day the patient complained of vertigo and nausea and felt very
tired. The next day repeated enuresis was reported. Agitation, signs of hepatic
encephalopathy and tarry stools appeared three weeks after onset. During the
next two days the patient deteriorated dramatically. All therapy was stopped
because of poor prognosis. The patient became comatose and died from hepatic
failure two days later. Autopsy was not performed. All attending doctors agreed
that the cause of death was fulminant hepatitis B, but it seemed debatable
whether this was an acute condition or an exacerbation of a chronic disease
that had already been present in 2001, but had been masked by the
immunosuppressive therapy for lupus erythematosus. Azathioprine induced
hepatotoxicity is another aggravating factor under discussion. The investigator
considered there was a reasonable possibility that the event may have been
caused by study medication.
·
Patient 3963
was a 45 year old Caucasian. Relevant medical history included constant atrial
fibrillation, left heart failure, congestive cardiomyopathy, chronic
bronchitis, paroxysmal ventricular tachycardia and an automatic implantable
cardioverter/defibrillator. Pre-study stroke prophylaxis consisted of warfarin.
As study treatment the patient was allocated to receive ximelagatran 36 mg
b.i.d. Approximately 28 weeks after commencing study medication the patient was
hospitalized with dyspepsia, nausea, vomiting, increased weight and girth. In
addition the pacemaker had been activated three times for the last few days
because of ventricular tachycardia. The condition was consistent with
deterioration of congestive heart failure with increased right heart failure,
peripheral edema and possible liver enlargement. Blood samples including liver
enzymes were taken. An ultrasound of the liver showed severe intra-abdominal
obesity and fatty liver. The slightly increased liver enzymes were assessed due
to hypoperfusion and liver stasis. The patient's treatment with diuretics and
antiarrhythmics was adjusted after which the condition stabilized. The day
before the planned discharge, the condition aggravated acutely with cardiogenic
shock. The patient was transferred to another hospital where in spite of
maximum inotropic support, the patient died. The patient died approximately
nine days after the onset of the event. Cause of death was cardiac failure and
shock. An autopsy has not been performed. The investigator considered there was
no reasonable possibility that the events may have been caused by study
medication. Additional safety surveillance resulted in the following
information: Approximately 6 months from start of study drug (day 190),
elevated LFTs were noted by the central laboratory: ALT 4.81 x ULN, AST 4.33 x
ULN, ALP 1.98 x ULN and Bil 2.77 x ULN. Repeat sampling on day 203 showed ALT
1.31 x ULN, AST 1.17 x ULN, ALP 1.36 x ULN, and Bil 1.77 x ULN. At this time
point the patient was re-hospitalized with deterioration of congestive heart
failure, as described above.
·
Patient 0430
was a 90 year old Caucasian. Relevant medical history included hypertension,
myocardial infarction, diabetes, lumbar pain, insomnia and bronchopneumopathy.
The reason for entering the study was an acute coronary syndrome with a peak
Troponin I value of 0.44 (ULN=0.04). The patient received ximelagatran 24 mg
b.i.d. and ASA 160 mg o.d. After four weeks on study drug the patient developed
right cardiac failure which was considered non-serious. After 17 days the event
was considered medically important and the patient was hospitalized. He
presented with bilateral lower leg edema and jugular turgescence. The patient
was hospitalized for worsening of right cardiac failure after 16 weeks on study
drug. He presented with edema. Study drug was withdrawn (total study drug
treatment was 18 weeks) and the patient died from right cardiac failure 3 days
after stop of study drug. No autopsy was performed. The investigator considered
that there was no reasonable possibility that the events may have been caused
by study medication or by other medication. Additional safety surveillance
resulted in the following information: Four and a half months from start of
study drug (day 132) elevated LFTs were noted by the central laboratory: ALT
4.42 x ULN, AST 6.35 x ULN, ALP 4.30 x ULN, and Bil 2.23 x ULN. ALT had been
slightly increased at start of study drug (1.33 x ULN), but was normal from day
8 until day 132. ALP was elevated throughout the study with a peak at the last
sampling on day 132. Bil was slightly elevated from day 84. The patient
experienced a minor conjunctival bleeding 11 days prior to the ALT elevation
and muscular pain 4 days prior to the ALT elevation. As described above, the
patient also had hematuria followed by worsening of right cardiac failure with
fatal outcome at the time of the ALT elevation.
·
Patient 4035
was a 76 year old Caucasian. Relevant medical history included previous VTE
event, hypertension, parkinsonism, pyeloglomerulonephritis and coronary
disease. The reason for entering the study was DVT. The patient received
ximelagatran 36 mg b.i.d. Fifteen weeks after start of study drug the patient
was hospitalized due to melaena, decreased haemoglobin and anaemia. HB was 8.6.
Bleeding from the digestive tract was suspected. Study drug was permanently
stopped. Blood transfusion (two units of blood) was given. Gastroscopy was
normal. The patient recovered from the bleeding and was discharged from
hospital one week after start of event. Hb was now 12.0 (normal for this
patient). Two weeks after discharge from hospital colonoscopy and
ultrasonography were done that revealed adenocarcinoma of colon. Four weeks
after stop of study drug the patient was hospitalized for operation of colon
adenocarcinoma and liver metastases in the right liver lobe. Resection of
sigmoideum and right liver lobe were done. After six days X-ray of abdomen
showed fluid levels. An abscess of the anastomosis was diagnosed and he was
re-operated. Four days later a multiorgan failure developed diagnosed with
abdominal ultrasound and x-ray. The patient was treated with antibiotics,
fluid, enoxaparin, blood, plasma and digoxin. He died the same day and the
probable cause of death was the multiorgan failure. The investigator considered
there was a reasonable possibility that the event bleeding from digestive tract
may have been caused by study medication, but that there was no reasonable
possibility that the events adenocarcinoma, liver metastases, abscess of
anastomosis and multiorganic failure may have been caused by study medication.
·
Patient 7859
(not included in the sponsor’s concomitant ALAT and bilirubin elevation
analysis) was a 77 year old Caucasian and initiated on ximelagatran 36 mg bid
treatment on 13 August 2001. Past medical history included a cholecystectomy,
duodenal ulcer, sick sinus syndrome, pacemaker insertion, hypertension, carotid
stenosis, abdominal aortic aneurysm repair (13 April 2001), and coronary artery
disease. On 15 October 2001 (day 63), safety laboratory results demonstrated
elevated liver transaminases: ALAT 216 U/L, ASAT 154 U/L; ALP was 156 U/L and
total bilirubin 1.3 (baseline 1.1) mg/dL. He took his last dose of study
medication in the evening on day 80. The next day (on 2 November 2001), the
patient awoke with stomach pain and light-headedness. Bowel movements produced
bloody stools. He was admitted to hospital that same morning. At admission, he
had pallor, blood pressure 76/45 mm Hg, and heart rate 103/min. Laboratory
tests showed hemoglobin of 7 g/dL, hematocrit 20%, prothrombin time 37 sec, INR
3.4, aPTT 69 sec, albumin 2 g/dL, ASAT 629 U/L, ALAT 569 U/L, ALP 173 U/L and
plasma melagatran was 0.25 mM (therapeutic range). During hospitalization, he
received vitamin K, packed red blood cells (19 units), fresh frozen plasma (15
units), cryoprecipitate (30 units) and fluids. On 03 Nov laboratory tests
showed hemoglobin of 9.6 g/L, hematocrit of 27.3%, prothrombin time 14.5 secs,
aPTT 53 secs and INR 1.1. Liver enzymes also decreased: ALAT 134 U/L, ASAT 236
U/L and ALP 49U/L, but bilirubin was 6.2 (5.6x ULN). The patient underwent a
gastroscopy that revealed a Bilroth II anastomosis. There was bleeding in the
pre-anastomotic area and epinephrine was injected to attempt to decrease the
bleeding. The same day (3 November 2001) he presented with signs of respiratory
failure. Echocardiogram showed 55% left ventricular function and no major
cardiac abnormalities. However, heart rate was 130 to 140/min. Vasopressors
were necessary to sustain blood pressure and diltiazem was given to decrease
the heart rate. Synchronized cardioversion failed 4 times to establish sinus
rhythm. Shock persisted despite resuscitation with fluids, 2 units of packed RBC,
10 units of fresh frozen plasma and 1 unit of platelets. Profound coagulopathy
occurred. A consulting surgeon deemed operation futile. Support was
subsequently withdrawn and the patient died on 3 November 2001. No autopsy was
conducted but the cause of death was considered to be hemorrhage. The
investigator assessed the event as possibly related to the study medications
and concluded that the liver problems contributed to the bleeding.
2.6.10 Deaths in
ximelagatran-treated patients with ALAT >3xULN
The number of deaths in
ximelagatran-treated patients having maximum ALAT >3xULN is 19 (3.6%,
19/531) and in patients having maximum ALAT <3xULN is 251 (251/6417,
3.9%) for central laboratory ITT population.
There was no apparent difference in the incidence of death between
ximelagatran-treated patients who experienced an increase in ALAT >3xULN
(3.6%) and those who did not (3.9%).
In addition to the 19
patients (19/531, 3.6%) who had ALAT >3xULN measured at the Central
laboratory subsequently died, an additional patient died after study closure
and is therefore not counted in the ITT analysis and a further 3 patients who
had ALAT >3xULN measured at a local laboratory subsequently died. Therefore, a total of 23 patients who had
ALAT >3xULN subsequently died. The one individual who had an hepatic SAE
leading to death was Patient SH-TPV-0002-265-5442 (see details above). ALAT was elevated 12 days after starting
study medication and he died 6 days thereafter from an acute hepatitis B
rapidly evolving to fulminant hepatitis.
This pattern of ALAT elevation was not consistent with the previously
observed pattern of elevations in patients exposed to ximelagatran. Although ximelagatran was not the cause of
the infectious hepatitis, the investigator could not rule out the possibility
that it aggravated the outcome. Two
other patients who died due to GI hemorrhage with severe coagulopathy had
elevated hepatic enzymes prior to death; both cases (patient 7259 and 7859)
were described above. Clearly, coagulopathy was due to ximelagatran and it
aggravated and contributed to these 2 patients’ deaths.
Patients who had ALAT >3xULN measured at the Central laboratory and
subsequently died are presented in Table 37.
Table 37: List of ximelagatran-treated patients
who had ALAT >3xULN measured at the Central laboratory and subsequently died
An additional patient
died after study closure and is therefore not counted in the ITT analysis.
Patient SH-TPC-0001-062-0286, an 82 year old female, died from AMI 2 weeks
after stopping study drug (ximelagatran 36 mg bid) due to a previous AMI.
A further 3 patients who
had ALAT >3xULN measured at a local laboratory subsequently died. These were as follows:
Patient
SH-TPA-0005-0050-8357, a 74-year-old female, died from sepsis while taking
ximelagatran 36 mg bid, and the temporary ALAT elevation was found during a
previous hospitalization for pneumonia.
Patient
SH-TPA-0003-217-2893, a 67-year-old male, died while taking ximelagatran 36 mg
bid due to acute cholecystitis and cardiac arrest. The reported SAE term was abdominal colic.
Patient
SH-TPV-0002-504-4035, a 76-year-old male, died due to multiorgan failure. The patient had been hospitalized for
operation of colon adenocarcinoma and liver metastases in the right liver lobe,
4 weeks after stop of study drug (ximelagatran 36 mg bid).
Seven of 19 cases
(#1793, 3963, 7259, 7859, 5442, 0430 and 2065) have been discussed above in
detail. Patient 2826 died from rupture of aorta and patient 6603 died 16 months
after discontinuing study drug.
2.6.11 Potential prognostic factors related to
ALAT >3xULN.
The multivariate
analysis of potential prognostic factors for the risk of ALAT>3xULN was
performed using a
logistic regression model with a stepwise selection algorithm. The following
factors were tested for inclusion; sex (female vs male), age, (>=75 vs
<75 years), weight (>=75 vs <75 kg), BMI (>=27 vs <27 kg/m2),
CrCL (>=80 vs <80 mL/min), ethnic origin (Asian vs rest, i.e. all
others), concomitant aspirin use (yes vs no), concomitant statin use (yes vs
no), and patient population (VTE-T vs rest, VTE-P vs rest and Post ACS vs rest,
AF was used as "baseline"). Stepwise analyses are presented in Table
38 (for patients in the ximelagatran group only).
Table 38: ALAT >3xULN, analysis of potential
prognostic factor, stepwise model
selection algorithm, (ximelagatran group only) (ITT population): LTE pool
From these analyses 6
risk factors were statistically significant for the ximelagatran group:
Post ACS population
(p=0.0009), VTE-T population (p=0.0003), use of statins (p=0.019),
BMI <27 kg/m2
(p<0.0001), non-Asian race (p=0.0038) and female sex (p=0.0002, 9.4% vs.
6.7%).
2.6.12 Relationship between exposure to
melagatran and ALAT elevation.
Exposure to melagatran
has been evaluated in patients in the non-surgical long-term studies. Individual melagatran AUCs were estimated by
population PK modeling. The distribution
of melagatran AUC in patients with an event is largely within the melagatran
AUC range in patients without an event.
These data suggest that for the patient population and doses studied
exposure is not predictive of ALAT >3xULN in individual patients.
The calculated
cumulative risk (hazard ratio) of an increase in ALAT for each unit increment
of AUC, in each pool, is shown in Table 39.
Except for the VTE-P and post ACS pools, there is a statistically
significant relationship between exposure and the risk of an ALAT elevation
above 3xULN in each pool.
Table 39 Relationship of melagatran AUC to
occurrence of ALAT elevation >3xULN
2.6.13 Summary of hepatobiliary toxicity
In patients receiving
long-term administration of ximelagatran (>35 days) an increase in
ALAT >3xULN occurred
in 6-13% (total: 531/6948, 7.6%) compared to 0-2% (total: 68/6230, 1.1%) of
patients receiving comparator treatments. ASAT increased in conjunction with
ALAT. The time pattern of ALAT elevations was consistent and typically occurred
between 1 and 6 months after the initiation of ximelagatran. Prior to and after
this time frame the incidence of ALAT increase was similar to comparators.
These data are based on ALAT sampling in 6840 patients.
Among the 531 patients
in the ximelagatran group who presented with an ALAT >3xULN, 206 (39%)
completed the study on study drug. The
remaining 325 patients (61%) discontinued study drug prematurely. The hepatic
transaminases returned to <2xULN in the majority of patients (95%), whether
the patient continued treatment with ximelagatran or not.
An evaluation of
potential risk factors for increase in ALAT indicated an increased risk in the
Post ACS (p=0.0009), and
VTE-T (p=0.0003) populations and also in female patients (p=0.0002) patients
with low BMI (<27 kg/m2) (p<0.0001) and patients receiving concomitant
treatment with statins (p=0.019); Asian patients were found to have a decreased
risk (p=0.0038). Although any single factor identified above may not be strong
enough to justify to excluding the subgroup population, the patients who have 2
or more risk factors should not be given ximelagatran, such as, female patients
with low body weight or who are taking statin.
ALAT >3xULN was
associated with bilirubin >2xULN (within one month following the rise in
ALAT) in 0.53% (37/6948)
of all patients who were exposed to ximelagatran >35 days as compared to 0.08%
(5/6230) of patients exposed to comparators (including 10 ximelagatran and 1
comparator by local laboratory measurement). A total of 14 ximelagatran-treated
patients (14/37, 35.1%) have no alternative explanation for concomitant ALAT
and bilirubin elevation. Concomitant elevations of ALAT >3xULN and bilirubin
>2xULN were observed during the first month of ximelagatran therapy in 6 of
37 patients. Nine of the ximelagatran-treated patients who had ALAT >3xULN
and bilirubin >2xULN (24.3%, 9/37) died with these elevations. Among them, 3
died from heart failure; 3 died from carcinomas with hepatic matastases; 2 (ID#
7259, and 7859) died from GI bleeding with coagulopathy and 1 (ID# 5442) died
from hepatitis B. One patient developed biopsy documented hepatic necrosis with
coagulopathy with a fatal outcome from a duodenal ulcer (#7259). Liver
failure/toxicity by ximelagatran might have caused or at least contributed to
these deaths.
In conclusion, safety
data on hepatobiliary toxicity does not support the safe use of ximelagatran
for long-term (>35 days) treatment of patients with AF or DVT for either 36
mg bid or 24 mg bid dosing.
2.7 Analysis of adverse events of pancreatic
effects
Pancreatic hyperplasia has been observed in pre clinical
studies in rats. A “pancreas sub-study” was performed as part of study
SH-TPA-0005 to determine if there was a safety concern for ximelagatran
regarding pancreatic hyperplasia. CCK
plasma concentrations were measured after approximately 3 months of receiving
study drug in a subset of patients. The
objective of this assessment was to determine whether ximelagatran was
associated with elevations in plasma CCK after a standard meal because this is
the mechanism by which rats undergo pancreatic trophic stimulation, possibly
leading to pancreatic adenomas and occasionally, pancreatic carcinoma. In addition, special abdominal CT scans were
performed, which were designed to measure pancreas volume, obtained prior to
drug exposure and then again after 12 months’ exposure to study drug. The objective of this assessment was to
determine whether long-term administration of ximelagatran was associated with
increased pancreas volume because a trophic effect on pancreas would yield
increased volume of pancreatic tissue.
2.7.1 CCK in
plasma – laboratory findings
A total of 130 patients (62 ximelagatran, 68 warfarin) were
enrolled in the CCK subset, of whom 119 (56 ximelagatran, 63 warfarin) provided
CCK plasma data at 3 months. Mean (SD)
CCK plasma concentration was 14.97±18.32 picomolar for the ximelagatran-treated
patients and 11.39±16.51 picomolar for the warfarin-treated patients. Median CCK plasma concentration was 6.63
(range 2.00 to 62.50) picomolar for the ximelagatran-treated patients and 4.50
(range 2.00 to 62.50) picomolar for the warfarin-treated patients. There was no statistically significant
difference in the plasma concentrations between the 2 groups, p=0.225 (Mann-Whitney test). The data were not normally distributed and no
transformations were applied and hence the Mann-Whitney test was used.
2.7.2
Pancreas volume – laboratory findings
Complete sets of pancreatic CT scans were available for a
subset of 34 patients in the ximelagatran group and 28 patients from the
warfarin group. The mean ±SD change from
baseline in pancreatic volume was -10.85±13.63 for the ximelagatran group
and -10.49±13.85 for the warfarin group
and was statistically significant for both treatment groups (p=0.0001 and
0.0004, respectively). However, the
between group comparison was not statistically significant, p=0.92 (Student’s
t-test). Pancreatic volume change over
one year did not correlate with CCK plasma concentration at 3 months. Treatment, CCK, and treatment-CCK interaction
did not affect pancreatic volume.
2.7.3
Analysis of AEs affecting the pancreas:
long-term exposure (LTE) pool
During the program, 13 patients (2 ximelagatran, 11
comparator) were diagnosed with a pancreatic cancer. Fifteen patients developed pancreatitis during active treatment in the
program (6 ximelagatran, 9 comparator). A further 2 patients had an AE of
pancreatitis in the follow-up period, one after treatment with ximelagatran
(SH-TPA-0003-096-2960) and one after treatment with warfarin
(SH-TPA-0005-2690-7288).
Taking into account both
the AE profile and the sub study data, there is no safety concern for
ximelagatran regarding pancreatic events.
2.8 Analysis of adverse events of coronary artery
disease
Patients with coronary
artery disease (CAD) adverse events are summarized in Table 40.
Table 40: Summary of patients with adverse events
of coronary artery diseases (safety population)
|
Population with
CAD AE
|
Ximelagatran
(AF, n=
3836)
(VTE-T,
n=1236)
(VTE-P,
n=612)
n %
|
Warfarin
(AF, n=
3719)
(VTE-T,
n=1248)
(VTE-P,
n=611 placebo)
n %
|
|
|
AF:
Total CAD
MI
|
268
7.0
62 1.6
|
248
6.7
52 1.4
|
|
|
VTE-T
Total CAD
MI
|
16
1.3
3 0.2
|
1
0.1
0 0
|
P=0.00024
|
|
VTE-P
Total CAD
MI
|
16
2.6
10 1.6
|
12
2.0
3 0.5
|
P=0.447
P=0.05131
|
|
VTE
Total CAD
MI
|
32 1.7
13 0.7
|
13 0.7
3 0.16
|
P=0.00411
|
VTE=VTE-T + VTE-P
In all study populations
except the post ACS, the proportion of patients with coronary artery disease
adverse events was higher in the ximelagatran groups than in the comparator
groups (7.0% and 6.7% for the AF pool, 1.3% and 0.1% for the VTE-T pool and
2.6% and 2.0% for the VTE-P pool, for the ximelagatran and comparator groups,
respectively). This trend was consistent
across the pools for myocardial infarction; however, the difference in event
rates (%/patient year) was small (0.9% and 0.6% for the AF pool, 0.6% and 0% for the VTE-T pool and 1.1% and
0.2% for the VTE-P pool, for the ximelagatran and comparator groups,
respectively). Proportion of patients with coronary artery
disease adverse events was statistically significantly higher in the
ximelagatran group (32/1848, 1.7%) than in the warfarin/placebo group (12/1859,
0.7%) in VTE (VTE-T + VTE-P) population (p=0.00411). Proportion of patients
with MI was also significantly higher in the ximelagatran group (13/1848, 0.7%)
than in the warfarin/placebo group (3/1859, 0.16%) in VTE population
(p=0.01183). There were no appreciable differences between the treatment groups
for underlying diseases including hypertension, hypercholesterolemia, diabetes
mellitus, coronary atherosclerosis, as well as age, gender and weight.
Considering ximelagatran as an anticoagulant with potential to treat MI, these
results are worrisome.
2.9
Clinical Laboratory Evaluations
The analyses of clinical
laboratory data in the individual studies in this application have not
identified any adverse findings with the exception of increases in LFTs.
Microscopic hematuria
was more common in the ximelagatran group than in the placebo group in the post
ACS pool; however, in the warfarin comparison pools there was no difference.
A reduction in
triglycerides, cholesterol and LDL was seen in the ximelagatran group in the AF
pool.
<
