Activated protein C as disease-modifying

therapy in antenatal preeclampsia:

An open-label, single arm safety and
efficacy trial
Presented By:

DEPARTMENT OF OBSTETRICS AND GYNECOLOGY

FACULTY OF MEDICINE SRIWIJAYA UNIVERSITY
Dr. MOH. HOESIN GENERAL HOSPITAL PALEMBANG
2018
Introduction

Preeclampsia is characterized by maternal systemic

inflammation and coagulation activation, akin to the sepsis
syndrome.

rhAPC may modify disease progression to safely prolong

pregnancies and improve perinatal outcomes.

Both maternal and perinatal risks are highest remote from

term.

We reviewed the evidence to support a safety and efficacy trial of rhAPC in

pregnant women with preeclampsia with <50% chance of intact perinatal survival to
safely prolong expectantly managed pregnancies
 Methods

It conducted solely at British Columbia

This was a pragmatic, single arm, Women’s Hospital and Health Centre
open-label, single center safety (BCW). It was approved by the Research
and efficacy trial Ethics Board at the University of British
Columbia
Methods
This was a trial in women with pregnancies complicated by early onset preeclampsia in
which the chances of either neonatal death or severe neonatal morbidity exceed 50%

1 Inclusion Criteria
women were included if they :
• had preeclampsia (maternal hypertension (BP > 140/90mm Hg measured twice,
at least 4 h apart) presenting at>20 weeks’ gestation with either >0.3 g/day of
proteinuria/ a random urinary protein : creatinine ratio of>3 g/mol)
Inclusion Criteria

• were at <27 weeks’ gestation and/or an estimated fetal

weight<600 g
• one or more organ dysfunctions affecting the cardiovascular,
renal, coagulation, central nervous, respiratory or hepatic
systems
Methods

2 Exclusion Criteria

Women were excluded if they had/were :

• a contraindication to prolonging pregnancy for maternal or fetal reasons
• lethal or life-threatening fetal anomaly or congenital infection
• current bleeding
• increased risk for bleeding
• A known hypercoagulable state
Exclusion Criteria

• inability to give informed consent or presence of an advanced directive to withhold life-

sustaining treatment
• other significant immune disorders
• HIV positive
• Undergone bone marrow, liver, pancreas, or small bowel transplantation
• age<18 years
• weight>135 kg
Methods

Following signed consent, eligible women received rhAPC, infusion ran at 24

μg/kg/hr for up to 96 h antenatally.

Women without bleeding began the infusion immediately.

Women with suspected/confirmed antepartum hemorrhage (APH) were

eligible to commence the infusion>48 h after last concern about active
bleeding.

Low dose heparin was not a contraindication. Wait times of >8 h after
the most recent dose of unfractionated heparin or >12 h since the last
dose of LMWH were implemented
Methods

We planned to stop the infusion under the following circumstances:

• patient request • 2 h prior to a scheduled Cesarean

• inadequate nursing coverage
• suspected/ confirmed APH
• evidence of bleeding from any other
site
• Onset of labor
• commencement of an induction of
labor
section, a regional anesthetic or
removal of an epidural catheter
• immediately, should an emergency
Cesarean section be indicated
• the occurrence of a eclampsia
• INR>3.0
• platelet count<30×109/L
• ultrasound evidence of a hepatic
hematoma.
 Methods

Women were provided with a

minimum of one-on-two nursing in the
close surveillance area of the delivery
suite for the duration of the infusion
vital signs were assessed every
30 min while the woman was
awake and every 60 min when
asleep, including symptoms and
signs of APH
Urine output was measured hourly.
Methods
Baseline investigations :
• complete blood count (CBC),
coagulation profile, renal and
liver function tests.
• These were repeated 6 h after
the beginning of the infusion,
and at least 12 hourly thereafter.
• Spot urines were sent daily for
urinary protein:creatinine ratios.
Fetal assessment :
• a baseline non-stress test,
ultrasound estimation of fetal
weight, amniotic fluid index (AFI)
and umbilical arterial Doppler
studies before commencing the
infusion.
• Non-stress test, AFI and Doppler
studies were repeated daily until
delivery, with other monitoring at
physician discretion.
Methods

The primary safety outcome

the incidence of peripartum bleeding, where bleeding was defined both as ‘estimated
blood loss>1 L’ and ‘blood loss requiring transfusion.’

The primary efficacy outcome

the duration of pregnancy from the time of enrolment in comparison with the current
standard of care, which is expectant therapy
The secondary outcomes were:

(i) death or serious maternal complications,

(ii) markers of maternal illness;
(iii) the incidence of hemorrhage (antepartum, intrapartum, and postpartum);
(iv) Perinatal mortality and significant neonatal morbidity; and
(v) biomarkers of coagulopathy and inflammation.
Methods

Assess efficacy
• we selected matched cases from the fullPIERS cohort who had been
admitted to BCW
• Controls were women who met eligibility criteria for the trial, and were
matched 2:1 or 1:1 for maternal age (±5 y), gestational age on admission
(±2 wk), parity (0, 1, ≥2), and abnormalities in serum creatinine, platelet
count, and aspartate transaminase.
 Methods

Assess biomarkers
we selected pregnant women with preeclampsia with adverse conditions who
were receiving expectant management and who remained naïve to rhAPC
The following biomarkers of disease severity were assessed:
(i) markers of coagulopathy (fibrinogen, TAT, and PAI-1);
(ii) thromboelastogram;
(iii) markers of angiogenic balance;
(iv) cytokine markers of inflammation;
(v) total protein C concentration in human breast milk.
Methods

Statistics
• Descriptive statistics were calculated and compared with either PIERS
dataset controls (clinical) or APC-naïve biomarker controls.
• Serial measures of biomarkers were analyzed and compared using the
Holm-Sidak method of multiple T-test comparisons.
• Continuous variables were compared by Wilcoxon rank sum test, Mann-
Whitney U test or student’s T-test
• Dichotomous variables by Fisher’s exact test,
• Survival analysis by Mantel-Cox and Gehan-Breslow-Wilcoxon Tests
using GraphPad Prism 5.04
Results

12 eligible women were recruited to the trial

31.6% of 38 eligible women approached for participation from
December 2004 to April 2009

3 did not receive the infusion due to a

shortage of nursing staff

9 women received rhAPC

16 contemporaneous and matched we recruited 6rhAPC-naïve women to
clinical controls were obtained from the act as biomarker controls (2009–2014).
BCW cohort within the fullPIERS
database (2003–2016)
 Results
Characteristic rhAPC-treated rhAPC-naïve clinical rhAPC-naïve Wicoxon or Fisher’s
(n=9) controls biomarker exact P
median (IQR) (n=16)* controls (n=6) (rhAPC vs clinical
or n (%) median (IQR) or n (%) controls)
Maternal age at EDD y 36 (30–39) 36 (32–37) 32 (23–35) 0.758
GA at admission wk 25.3 (24.8– 25.6 (25.0–26.2) 27.3 (25.6–29.4) 0.426
25.7)
Nulliparous Y 4 (44) 8 (50) 6 (100) 1.0
Multiple pregnancy Y 1 (11) 0 (0) 1 (17) 0.36
Antenatal corticosteroids Y 9 (100) 13 (81) 6 (100) 0.28

Antihypertensives used Y 9 (100) 14 (88) 6 (100) 0.52

MgSO4 used Y 8 (88) 12 (75) 4 (67) 0.62
Prepregnancy weight kg 69.1 (55.9– 77.0 (56.8–82.3) 81.6 (62.9–82.7) 0.84
89.4)
GA at infusion eligibility wk 25.4 (24.8– 25.6 (25.0–26.3) 27.3 (25.6–29.4) 0.50
25.8)
fullPIERS probability at 1.3 (0.6–23.0) 5.2 (0.7–30.6) 1.4 (0.8–3.3) 0.43
infusion
eligibility %
 Results
Characteristic rhAPC-treated (n=9) rhAPC-naïve clinical rhAPC-naïve Wicoxon or Fisher’s
median (IQR) or n (%) controls biomarker exact P
(n=16)* controls (n=6) (rhAPC vs clinical
median (IQR) or n (%) controls)
Highest sBP mm Hg 158 (153–194) 169 (154–173) 163 (160–189) 0.36
Highest dBP mm Hg 105 (95–110) 102 (96–104) 112 (109–116) 0.30
Dipstick proteinuria + (0.5–4) 3 (1–4) 2 (1–3) 0.69
3
O2 saturation (pulse 97 (95–98) 97 (95–97) 97 (97–97) 1.00
oximetry) %
Total leukocyte 13.0 (9.5–16.1) 11.2 (10.2–15.3) 10.1 (8.2–14.5) 0.73
count×109/L
Platelet count×109/L 243 (151–263) 216 (157–276) 201 (159–260) 1.00
Fibrinogen μmol/L 4.27 (4.13–6.65) 4.21 (4.15–5.68) 4.39 (2.45–5.07) 0.36
INR 0.93 (0.92–0.94) 0.93 (0.92–0.94) 0.89 (0.86–0.90) 0.98
Serum creatinine 63 (44–80) 63 (53–73) 62 (50–68) 0.45
μmol/L
Serum uric acid 353 (281–380) 341 (333–361) 315 (291–371) 0.91
mmol/L
Aspartate 47 (28–88) 48 (24–112) 41 (22–85) 0.82
transaminase U/L
Lactate 774 (625–936) 661 (590–1077) 542 (432–715) 0.65
dehydrogenase U/L
Plasma albumin g/L 29 (28–34) 29 (27–33) 31 (26–34) 0.74
Total bilirubin μmol/L 7 (4–8) 7 (6–9) 7 (3–9) 0.23
 Results
Characteristic rhAPC-treated (n=9) rhAPC-naïve (n=16)* P-value
Primary safety outcome: antepartum/ 0 (0%) 0 (0%) –
intrapartum/postpartum
hemorrhage (%)
Primary efficacy outcome: infusion 175 (88–276) 86 (63–108) 0.077
eligibility to delivery (h)
Maternal Outcomes
Maternal death (%) 0 (0%) 0 (0%) –
Cesarean section (%) 9 (100) 14 (88%) 0.52
GA at delivery 26.6 (25.4–27.3) 26.3 (25.6–26.7) 0.76
Time on infusion (h) 95 (57–96) – –
Urine output over first 12 h (mL/h) 154 (44–221) 63 (45–76) 0.039
Fluid balance pre-infusion (mL/h) 43 (13–72) – 0.039 (pre- vs during)
Fluid balance during infusion (mL/h) 17 (-70–38) –
Maternal adverse outcomes 4 (44%) 5 (31%) 0.76
Ascites ×3 Acute renal failure ×1
Pulmonary edema × 1 Platelets < 50 × 109/L ×1
Blood transfusion ×2
Placental abruption ×1
Perinatal Adverse Outcomes
Birth weight (g) 550 (415–651) 630 (582–680) 0.20
Stillbirth (%) 0 (0%) 0 (0%) –
Neonatal death (%) 2 (22%) 2 (13%) 0.60
Neonatal morbidity (%)† 6 (86%) n=7 10 (63%) n=14 0.62
BPD×6 BPD×8
IVH×2 IVH×1
NEC×0 NEC×2
ROP×4 ROP×4
Results
Results

• 9 women received rhAPC (24 μg/kg/hr for ≤96 h antenatally)

• No safety issues were identified
• There was a marginal prolongation in eligibility-to-delivery
intervals for women receiving rhAPC
• Compared with both the pre-infusion phase in the rhAPC-treated
women themselves and with fullPIERS rhAPC-naïve women,
rhAPC was associated with increased urine output during the
infusion
Conclusions

• rhAPC appears safe and causes antenatal diuresis and may prolong
pregnancies compared with women with similar disease severity
managed in the same hospital.
• These data support further investigation of APC in women with severe
early-onset preeclampsia
• Following the withdrawal of Xigris®, recombinant purified human APC is
available
• In addition, these data will inform the design and implementation of
randomized controlled trials aiming to modify and/or moderate the
proinflammatory and proacoagulant state of preeclampsia.
 添加标题
Critical Appraisal

Questions Answers Explanation

1. Study design, This was a • Trial of rhAPC in consenting pregnant women

survey or pragmatic, single with severe early-onset preeclampsia.
registration? arm, open-label, • Disease severity-matched rhAPC-naïve
single center controls were identified from an existing
safety and efficacy database.
trial • An additional six women were recruited as
biomarker controls.

2. Inductive or Deductive Researcher collect all related theory/literature

deductive reasoning  design material and methodcollecting data
reasoning?  analyze  give conclusion
 添加标题
Critical Appraisal

Questions Answers Explanation

3 and 4 The primary safety outcome was the incidence of

Type and scales of each Nominal peripartum bleeding
variables in this study (characteristics and The primary efficacy outcome was the duration of
outcomes) pregnancy from the time of enrolment in comparison
with the current standard of care

The secondary outcomes were:

(i) death or serious maternal complications,
(ii) markers of maternal illness;
(iii) the incidence of hemorrhage
(iv) Perinatal mortality and significant neonatal
morbidity; and
(v) biomarkers of coagulopathy and inflammation
 添加标题
Critical Appraisal

Questions Answers Explanation

5. Type of data, primary, Primary data Primary data :

secondary or tertiary resources 9 women received rhAPC
resources? 16 contemporaneous and matched clinical controls
were obtained from the BCW cohort within the
fullPIERS database
6 rhAPC-naïve women to act as biomarker
controls

6. Group or ungroup data? Group Data rhAPC-treated (n=9)

rhAPC-naïve clinical controls (n=16)
rhAPC-naïve biomarker controls (n=6)
7. Ad hoc or routine data? 9 women received rhAPC from Desember 2004- April 2009
16 matched clinical controls (2003–2016)
6 rhAPC-naïve women as biomarker controls (2009–2014)
8. Measures of Central Main outcome measures: Primary safety outcome: incidence of
Tendency, Position and peripartum bleeding; primary efficacy outcome: duration of pregnancy
Dispersion after enrolment.
 添加标题
Critical Appraisal

Questions Answers Explanation

9. Tables that was Comparative table among groups of data
used to present
results of this
study
10. Graph used in this Line graphs The graphs present Kaplan-Meier survival
paper analysis comparing eligibility-to-delivery intervals
between women to whom rhAPC was
administered and matched rhAPC-naïve controls
from the BC Women’s fullPIERS cohort
11. Quality of High quality 1. The materials and methods for this study are
research data good and expressed in details.
2. A lot of considerations on interventions
3. The methods of meassurements are valid
4. They used data from reliable sources and
previous trials
添加标题
Critical Appraisal

Questions Answers Explanation

12. Bias the women recruited may not be representative of those
who might have received rhAPC in either a RCT or
clinical practice
Given the withdrawal of rhAPC (Xigris®) from the
market, such a RCT is unlikely to occur

13. Sample size 9 women Twelve (31.6%) of 38 eligible women consented; 3 did
calculation for not receive the infusion due to staffing. Therefore, 9
this study women received rhAPC

14. Sampling Purposive The reseachers looking for women who meet the
technique sampling inclusions and exclusions criteria
 添加标题
Critical Appraisal

Questions Answers Explanation

15 and 16. • Serial measures of biomarkers were analyzed and compared using
Statistical analysis the Holm-Sidak method of multiple T-test comparisons.
• Continuous variables were compared by Wilcoxon rank sum test,
Mann-Whitney U test or student’s T-test
• Dichotomous variables by Fisher’s exact test,
• Survival analysis by Mantel-Cox and Gehan-Breslow-Wilcoxon Tests
using GraphPad Prism 5.04

17. Error to conclude P < 0.05 was used for statistical significance
statistical analysis results
18. How was the • The presentation of results in this paper are summarized into
presentation of results in two table; baseline characteristics and outcomes.
this paper? • The tables present systematics data, easy to compare each
groups
• A graph is included in the paper to define comparison between
groups