Landmark trials Flashcards
TRUFFLE - the trial of umbilical and fetal flow in Europe
Give author, publication date and aim of trial
C Lees et al Lancet 2015 (Data collect 2005-2010) Establish if changes in fetal ductus venosus doppler waveform could be used as indications for delivery instead of CTG short term variability.
TRUFFLE - the trial of umbilical and fetal flow in Europe
Method and outcome
3 arm multicentre unblinded RCT with 542 babies.
Inclusion criteria: 26-31+6 weeks
<10th centile EFW but >500g
AbN UAPI
Excluded if known fetal abnormality.
Trial arms comared when to deliver:
Reduced STV CTG (<29w 3.5mS, >29w <4mS)
Early DV changes pulsatility index >95th
Late onset DV changes - absent a wave.
Primary outcome - survival free of neuro-impairment at 2 years old.
Secondary outcomes: Death in utero, neonatal deaths.
TRUFFLE - the trial of umbilical and fetal flow in Europe
Results
No significant difference between groups for the primary outcome ( survival free of neuro-impairment at 2).
CTG 77%
DV p95 84%
DV a wave 95%
DV a wave group’s increase in survival free of neuro-impairment but this was accompanied by a non significant increase in perinatal and infant mortality.
TRUFFLE - the trial of umbilical and fetal flow in Europe
Strengths
Randomised multi-centre, European
Intention to treat randomisation
Independent review of data yearly
Peads blinded to the groups
TRUFFLE - the trial of umbilical and fetal flow in Europe
Weaknesses
Outcomes may be underpowered partly due to safety net triggers (AREDF UAPI or abN CTG) in 50% of late DV changes group compared to 38% in other groups
Women closely looked after by MFM may not be generalisable
CTG monitored group was based on competerised assessment on STV not everywhere has access to this.
LACE - Laparoscopic approach to cancer of the endometrium
Authour, date, publication and aim
Janda et al
JAMA 2017
Aim - to investigate whether TLH is equivalent to TAH in women with treatment niave endometrial cancer.
LACE - Laparoscopic approach to cancer of the endometrium
Methods inclusion and exclusion criteria
MUlticentre, randomised equivalence trial
In OZ, NZ & HK
760 women randomised
TAH 353 vs TLH 407
Intention to treat analysis
Inclusion criteria - Stage 1 endometroid adenocarcinoma of the endometrium (FIGO)
Excluded - any other histology, bulky LN on imaging and uterine size >10 weeks.
LACE - Laparoscopic approach to cancer of the endometrium
Primary and secondary outcomes
Primary outcome:
Disease free survival (interval between surgery and date of recurrence) acknowledging disease progression, development of new primary cancer and death assessed at 4 years.
Secondary outcomes:
Recurrence of endometrial cancer and overall survival.
LACE - Laparoscopic approach to cancer of the endometrium
Results
No statistically significant difference in disease free survival
81.3% TAH vs 81.6% TLH
No difference in recurrence of endometrial cancer
Overall survival no difference
Intra-op adverse events less frequent in TLH
Costs lower in TLH
TLH 6% converted to laparotomy
LACE - Laparoscopic approach to cancer of the endometrium
Strengths and weaknesses
Strengths: Randomised Prospective Large, multicentred Appropriately powered Oz/NZ population Credentialing system to ensure proficiency Limitations: Unable to blind surgeons or patients LN dissection was left to discretion of surgeon ?impact on survival
Provision of no cost long acting contraception and teenage pregnancy
Author, publication and date and aim
Gina et al
NEJM 2014
Aim - To determine if promotion and access to no cost long acting reversible contraceptive methods would reduce unintended teenage pregnancy in the St Louis region when compared with national rates.
Provision of no cost long acting contraception and teenage pregnancy
Methods and inclusion criteria
Prospective cohort study of 1404 teens from 2007 till 2011.
Standardised counselling
Then provided with their preference at no cost
Follow up via telephone 6 monthly for 2-3 years.
Inclusion criteria:
Age 14-19 years old
English or Spanish speaking
Resided or sought healthcare in St Louis
Sexually active with male or plans to be within 6 months
No desire for pregnancy in next 12 months
Provision of no cost long acting contraception and teenage pregnancy
Primary and secondary outcomes and results
Primary outcomes - pregnancy, live birth rate and abortions
Secondary - Subanalysis of age and race
Results:
72% chose IUD or implant
Pregnancy rates 34 per 1000 vs 158.5 per 1000 (4.6 times higher)
Abortion rates 9.7 per 1000 vs 41.5 per 1000 (4.2 times higher)
Provision of no cost long acting contraception and teenage pregnancy
Strengths and limitations
Good follow up rates 92%, 82% and 75% at 3 years.
Limitations pregnancy rates self reported so could be under reported.
Teens surveyed regularly which may have influenced adherence.
ARRIVE - A randomised trial of induction vs expectant management
Author, publication date and aim
WA Grobmen
NEJM 2018
To test the hypothesis that elective IOL at 39 weeks would result in a lower risk of composite outcome of perinatal death or severe neonatal complications than expected among low risk nulliparous women.
ARRIVE - A randomised trial of induction vs expectant management
Inclusion criteria and method
Multicentre, randomised parallel group trial in 41 USA hospitals
Inclusion: P0 34 to 38+6 weeks
Singleton cephalic
No contraindication to NVD
Low risk meant no condition that would indicate delivery before 40+5
Expectant group no delivery before 40+5 but to have it started prior to 42+2
No specific induction protocol was mandated for either group.
ARRIVE - A randomised trial of induction vs expectant management
Results
No statistically significant different in composite outcome of perinatal death or severe neonatal outcomes between groups.
Lower frequency of c sections 28 IOLs needed to prevent 1 c-section
Lower hypertensive disorders
In women with unfavourable bishop score IOL still resulted in lower c-section rate compared with expectant.
ARRIVE - A randomised trial of induction vs expectant management
Strengths and weaknesses
Strengths: Large trial >6000
Randomised data from previous observational studies
Weaknesses: unmasked were neonatal complications less likely to be discovered in NVD group due to bias from peadiatric doctors.
Cost implications are 28 IOLs worth it to prevent 1 c-section
Method nt mandated ?misoprotol
MAGPIE - RCT placebo controlled Lancet 2002 multinational
Aim - to determine if women with PET or their children or both do better f given MgSO4 antenatally of within 24 hours PP if BP >140/90 and clinician unsure.
Results - reduced eclampsia by 58% NNT 91 overall or 63 with severe BP
- Maternal mortality lower RR 45% (in income poor countries)
- 24% women got side effects from MgSO4 flushing being the most common. More common with IM preparation.
- No clear difference in length of stay in hospital or use of hospital resources
- No clear difference difference in length of stay in hospital or use of hospital resources
- No clear difference in risk of baby dying
- Lower risk of abruption with MgSO4 by 27%
ACTORDS - Neonatal RDS after repeat exposure to antenatal corticosteroids: an RCT. Crowther Lancet 2006
Aim - to establish if repeat prenatal corticosteroids given to women at high risk of preterm birth can reduce neonatal morbidity without harm.
Intervention those included were >7 days after receiving first course of prenatal corticosteroids randomised to either IM 11.4mg Betamethasone vs placebo given weekly if woman remained undelivered ad less than 32 weeks and stil at ongoing risk of preterm birth.
Results:
Steroid group - less RDS NNT 14
- Fewer severe lung disease NNT 14
- Less O2 therapy NNT 15
- Shorter duration of mechanical ventilation
No difference in - Chorioamnionitis requiring IV Abx
- weight at birth and discharge
- Length of NICU stay
ALIFE: Aspirin plus Heparin or aspirin alone in women with recurrent miscarriages Kaandarp NEJM 2010
Multicentre RCT with 3 arms interventions vs placebo 360 women. Recurrent miscarriage defined as 2+.
Results - no difference in live birth rates:
Aspirin + LMWH 54%
Aspirin 50%
Placebo 57%
Those receiving combination therapy delivered around 1 week earlier and a tendency to bruise and itch.
A comparison of Medical management with Misoprostol and surgical management for early pregnancy failure.
Zhang et al NEJM 2005
Multicentre RCT in USA Stratified randomisation 3:1 Medical:surgical.
Primary outcome - no need for further evacuation t 30 days.
Results:
- Success rate 84% Medical
- Success rate 97% Surgical
No difference in rate of infection or bleeding requiring transfusion.
Similar rates of acceptability between women.
Prophylactic administration of 100mg progesterone by vaginal suppository to reduce the incidence of pre-term birth in women with increased risk: An RCT placebo controlled trial.
da Fonseca et al American Journal of O&G 2003
Inclusion criteria: Previous preterm birth, uterine malformation or prophylactic cerclage.
Results:
- Pre-term birth rate overall 21%
Progesterone 13.8% vs placebo 28%
For delivery under 34 weeks 2.8% progesterone vs 18.6% placebo
No difference in admission with TPTL labour progesterone progesterone group more likely to be pregnant 72 hours later.
Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus
Doyle et al Cochrane 2009
Included 5 trials: Pre Mag Trial, ACTONMgSO4, MAGPIE, MAGNET and Beam Rouse.
Results:
Reduced risk of cerebral palsy NNT 63
MgSO4 had no overall effect on pediatric mortality
No difference in serious adverse maternal outcomes but more women on MgSO4 ceased therapy due to side effects.
Most significant outcomes occurred for those under 34 weeks.
Protocol loading dose 4g over 20mins then 1g per hour for 24 hours stop if birth has not occurred or is imminent. Give further loading dose if preterm birth starts again 6 hours later.
200mg Progesterone and risk of preterm birth among women with a short cervix
Fonesca NEJM 2007
Women had to be asymptomatic with a short cervix <15mm at 20-25 weeks.
Multi-centre double blinded placebo trial.
Results:
Spontaneous delivery <34 weeks less frequent in progesterone group 19.2% vs 34.4%
Especially if no history of PTB and singleton.
OPPTIMUM Trial 2016 - largest trial looking for progesterone and pre-term birth showed it did not reduce risk.
Antenatal betamethasone for women at risk of late preterm delivery
Gyamfi-Bannerman NEJM 2016
RCT multicentre
Late preterm 34 to 36+6 weeks
Primary outcome composite for any respiratory support within first 72 hours, (stillbirth and neonatal death but there were none)
Results: Lower neonatal composite 11.6% vs 14.4% NNT 35.
Severe respiratory complications 8.1% vs 12.1% NNT 25.
Less resuscitation and surfactant requirement
Shorter stay in NICU
Increased neonatal hypoglycemia
No difference in chorio or neonatal sepsis
TERM BREECH - Planned c-section vs planned vaginal birth for breech presentation at term. Randomised multicentre trial.
Hannah et al The Lancet 2000
Primary outcome - Perinatal mortality, neonatal mortality <28 days, serious neonatal morbidity.
In planned breech group only 56.7% delivered vaginally
Results:
Lower risk of combined neonatal outcome in planned c-section group NNT 14 (7 if country with low perinatal mortality)
RR 0.36 serious neonatal morbidity.
No significant difference in maternal outcomes.
HYPITAT - Induction of labour vs expectant monitoring for gestational hypertension or mild PET after 36 weeks.
Koopmans et al Lancet 2009
Multi-centered open-label randomised trial.
Primary outcome - composite measure of maternal morbidity, mortality and progression to severe disease and major PPH
Results:
Half of those randomised to expectant had IOL anyway (for severe PET, HELLP, fetal distress, PROM, Post-dates)
Composite was better for IOL group 30% RR NNT 8
Improvement based on significant reduction for the need for anti-hypertensives and progression to severe PET.
Neonatal outcome equivalent in 2 groups.
TERMPROM - Induction of labour compared with expectant management for prelabour rupture of membranes at term if no evidence of fetal or maternal compromise.
Hannah et al NEJM 1996
4 interventions:
1. Labour induced immediately with oxytocin
2. Labour induced immediately with prostaglandins
3. Expectant management with IOL if needed via oxytocin
4. Expectant management with IOL if needed via prostaglandins.
Primary outcome - definite or probable neonatal infection
Results - No difference in rates of neonatal infection
Women induced with oxytocin had lower rates of maternal infection, less abx use and less postpartum fever
No difference in c-section rate
ASTECS - Antenatal betamethasone and incidence of neonatal respiratory distress after elective c-section: pragmatic randomised trial.
Stutchfield et al BMJ 2005
C-section >37 weeks singleton
Primary outcome - admission to special care unit with respiratory distress
Results:
RR 0.46 in favour of steroids for admission to NICU.
TTN reduced in steroid group RR0.54
Incidence of RDS RR0.21 in favour of steroids
Predicted probability of admission reduced with or without steroids from 37 to 39 weeks.
AN Betamethasone and delayed delivery until 39 weeks both reduce admission to SCBU after elective c-section.
A randomised trial of planned c-section of vaginal twin pregnancy
Barret 2013 NEJM
Inclusion 32 - 38+6 leading twin cephalic EFW 1500-4000g
Primary outcome: Composite of neonatal death and morbidity. Composite of maternal death and morbidity.
Results:
No difference in neonatal or maternal outcome.
Risk of EMLSCS in vaginal group 40%
Risk of EmLSCS for 2nd twin 4.2%
Effect of screening on ovarian cancer mortality: the prostate, lung, colorectal and ovarian cancer screening RCT.
Buys et al JAMA 2011
Women aged 55-74 years old
Had annual CA125 6 years and TVUSS 4 years
Results:
Simultaneous screening with CA125 and TVUSS did not reduce ovarian cancer mortality.
Majority of cancer in both groups 75-80% were high grade.
False positive screening results were associated with a high risk of complications ~15% at time of surgery.
Ovarian conservation at the time of hysterectomy for benign disease
W. Parker et al ACOG 2005
Aim - identifying the age at which oophrectomy might be recommended to women at average risk of ovarian cancer.
Retrospective cohort of 40-80 year old women followed in 5 yearly cycles from time of surgery till 80 years old.
Four groups:
1. Oophrectomy + oestrogen
2. Oophrectomy - oestrogen
3. Conservation + oestrogen
4. Conservation - oestrogen
Primary outcome all cause mortality.
Results:
Ovarian conservation - oestrogen reduces CHD and Hip fracture. Only slight 0.47% increase from ovarian cancer death.
65 years old not statistical significance favouring removal at this point.
Million Women study summary
Population based prospective cohort of women aged 50 years and over invited to breast cancer screening in the UK.
Breast cancer:
extra 5 per 1000 women after 10 years of oestrogen
extra 19 cases per 1000 after 10 years of combined HRT
background incidence 32 per 1000 women
Endometrial cancer:
2 per 1000 less on continuous combined HRT
4 more per 1000 women on oestrogen between 50-65 years old
Background incidence 5 per 1000
Criticism:
Previous HRT use was not accounted for and endometrial cancer risk persists for many years after cessation of HRT.
WHI study summary
Prospective cohort study looking at general health in postmenopausal women in USA. Through RCTs assessed the effect of HRT on heart disease, fractures, breast and endometrial cancer. The duration was 6 years.
Outcomes:
Breast cancer 28% increase with combined HRT where as oestrogen only was non significant.
VTE 18 in 10,000 additional women per year developed VTE per year when using combined HRT
Coronary heart disease if HRT commenced within 10 years of menopause no increase. But is increased if started later.
CVA increased with HRT.
Criticisms:
Average age was 62.5 and participants were not screened for co-morbidities e.g. hypertension
The Scottish Pregnancy Intervention Study (SPIN)
Clark et al 2010
Multicentre RCT
To assess whether enoxaparin and low dose aspirin after +ve pregnancy test and uss with intensive pregnancy surveillance reduced pregnancy loss rates vs intensive surveillance alone in women with a history of 2 or more consecutive miscarriages.
Secondary outcome:
Tolerance and safety of enoxaparin
Carriage of common thrombophilias
Results:
22% pregnancy loss rate in pharmocology group, 20% loss rate in surveillance group - no difference.
No safety issues with LMWH. Prevalance of common thrombophilias in this group of women similar to general population.
CLASP
RCT low dose aspirin 60mg vs placebo started at 12-32 weeks for prevention or treatment.
Double blind RCT for the effects of aspirin on proteinuric pre-eclampsia developing after randomisation.
Statistically significant in those that entered the study before 20 weeks for prophylaxis. NNT 100.
Effect of aspirin on preterm delivery reduced likelihood by 8%
No change in rates of IUGR
No effects on stillbirth
No safety concerns found with aspirin such as abruption APH
All outcomes were statistically significant for early onset PET <32 weeks.
HAPO - Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO) NEJM 2008
Whether maternal hyperglyceamia that was less severe than outright diabetes mellitus (defined at that time) was associated with an increased risk of adverse pregnancy outcomes. Multicentre, multi country observational study. Outcomes increased as per trial: - Birthweight >90th centile - Primary c-section - Clinical neonatal hypoglycaemia - Prematurity - Shoulder dystocia - PET - NICU admission - Hyperbilirubineamia
ACHOIS Effect of treatment of GDM on pregnancy outcomes NEJM 2005
To establish that screening and treatment of women with gestational diabetes reduces the risk of perinatal complications. RCT intervention (dietary advice, glucose monitoring and insulin) vs routine care. Composite serious neonatal outcomes were lower in intervention group 1% vs 4% NNT 34.
ORACLE 1
Kenyon et al Lancet 2001
Does administration of antibotics to mother in the context of pPROM improve neonatal health and long term child health by preventing infectious morbidty in the fetus or delay progression of pre-term birth.
Interventions 4 groups:
250mg erythromycin
325mg Augmentin
Augmentin and erythromycin
Placebo
Results:
Fewer primary neonatal composite outcome but non significant
Fewer delivered within 48 hours & 7 days
Reduction in treatment with surfactant
Fewer cerebral anormalities on USS before discharge
Fewer positive blood culture
Reduced incidence of NEC with erythromycin vs augmentin.
7 year follow up: The findings of decreased neonatal morbidity after the receipt of erythromycin in ORACLE I have not translated into long term benefit.
ORACLE 2: Broad-spectrum antibiotics for spontaneous preterm labour: the ORACLE II randomised trial
Kenyon et al Lancet 2001
Women in spontaneous preterm labor less than 37 weeks gestation, with intact membranes without evidence of clinical infection
Women were randomised to erythromycin, augmentin, both or placebo QID for 10 days.
Primary outcome was a composite of neonatal death, chronic lung disease or major cerebral abnormality on USS prior to discharge from hospital.
None of the antibiotic regimens were associated with lower rates of composite primary outcomes compared to placebo.
No prolongation of pregnancy.
Most women did not deliver with 48 hours (89.9%) or 7 days (84.6%) illustrates difficulty predicting PTL.
Antibiotics should not be prescribed to women in spontaneous preterm labor without any evidence of clinical infection as they will not improve neonatal outcomes or prolong the pregnancy.
PPROMPT
Aim to establish whetehr immediate delviery in singlton fetus with ruptured membranes close to term 34 - 36+6 reduces neonatal infection without increasing morbidity.
Intervention: Immediate IOL within 24 hours vs expectant management until 37 weeks.
Primary outcome: Definite or probable neonatal sepsis established by a review of the neonatal data by a central adjudication committee.
Results:
Definite or probably sepsis occured in 2% delivery vs 3% in expectant - not signifcant.
Neonates in the immediate IOL group had increased rates of respiratory distress and mechanical ventilation and spent more time in intensive care.
The women assigned to expectant group had higher risks of APH and use of post partum antibiotics and a longer hospital stay.
