Enhanced recovery pathways versus standard care after cystectomy - A Meta-analysis of the Effect on perioperative outcomes

1. E N H A N C E D R E C O V E R Y PAT H WAY S
V E R S U S
S TA N D A R D C A R E
A F T E R C Y S T E C T O M Y
A M E TA - A N A LY S I S O F T H E E F F E C T O N P E R I O P E R AT I V E O U T C O M E S
CHIA-CHING, CHEN
Journal Club, KFSYSCC, 2017/02/16

2. PART01
Objective
PART02
Evidence Acquisition
PART03
Evidence Synthesis
PART04
Conclusions
CONTENTS

3. PART
1
To perform a systematic review of the literature and a
meta-analysis comparing the effectiveness of ERAS
versus standard care on perioperative outcomes
after cystectomy
O B J E C T I V E

4. About the ERAS, and the context of the present study
N T R O D U C T I O N
I

5. MULTIMODAL
STANDARDIZED
INTERDISCIPLINARY
ERASABO UT

6. PHYSIOLOGICAL
PSYCHOLOGICAL
RESPONSES
MODIFY

8. Despite the significant body of evidence indicating that ERAS
protocols lead to improved outcomes, they challenge traditional
surgical doctrine, and as a result their implementation has been slow
WHY SLOW?

9. PREOPERATIVE
CONSELLING
1 2 3 4
OPTIMIZATION
OF NUTRITION
STANDARDIZED
ANALGESIC /
ANESTHETIC
REGIMENS
EARLY
MOBILIZATION
K E Y E L E M E N T S

10. PRE
• Readmission consoling
• Fluid and carbohydrate
loading
• No prolonged fasting
• No/selective bowel
preparation
• Antibiotic prophylaxis
• Thromboprophylaxis
• No premedication
INTRA
• Short-acting anesthetic
agents
• Mid-thoracic epidural
anesthesia/analgesia
• No drains
• Avoidance of salt and water
overload
• Maintenance of
normothermia (body warmer/
warm intravenous fluids)
POST
• Mid-thoracic epidural
anesthesia/analgesia
• No nasogastric tubes
• Prevention of nausea and
vomiting
• Avoidance of salt and water
overload
• Early removal of catheter
• Early oral nutrition
• Non-opioid oral analgesia/
NSAIDS
• Early mobilization
• Stimulation of gut mobility
• Audit of compliance and
outcomes

11. D AY B E F O R E R A D I C A L C Y S T E C T O M Y
Normal breakfast
Admit to hospital
Unrestricted clear fluids
Refer to dietician
Assess social circumstances and refer if needed

12. - Clear carbohydrate drinks up to 2
hours before surgery,
then nil by mouth
- Restart clear fluids as tolerated
when in recovery
- Start food chart
- Epidural analgesia in situ
DAY OF RADICAL CYSTECTOMYS
2
1
- Light diet as tolerated
- Mobilize and encourage self-care
(catheter care/flushing in
neobladders, and stoma bag
emptying in patients with a conduit)
- Free fluids as tolerated
- Female patients, remove vaginal
pack
- Mobilize and refer to
physiotherapist
- Ranitidine 3 times daily
intravenously or twice daily orally
- Remove drain if draining <50 mL in
24 hours
- Flush 20 mL into neobladder, twice
hourly for 12 hours and then 4 times
hourly

13. - Dietician to assess nutritional
requirements on day 5
- If a patient is not eating or drinking
after 5 to 6 days, but with bowel
activity, then start nasogastric
feeding
- If there is no bowel activity then
start total parenteral nutrition
3-4
8
5-7
- Remove epidural on day 3
- Continue to mobilize and
encourage self-care
- Light diet as tolerated
- Start planning for discharge
Stents out (no stentogram)
Remove clips 10

14. DAY 11-14
Continue as previous and schedule for return to home

15. BACKGROUND
CYSTECTOMY WITH URINARY DIVERSION

16. AIM OF ERAS
IMPROVE
SURGICAL OUTCOMES
BY
REDUCING VARIATION
IN
PERIOPERATIVE
BEST PRACTICES

17. REDUCE THE LENGTH OF STAY?
SHORTEN THE TIME TO RECOVERY OF BOWEL
ACTIVITY?
LOWER THE RATES OF READMISSION
VARIABILITY IN STUDY RESULTS
ABSENCE OF EXPERIMENTAL DATA
FROM RANDOMIZED, CONTROLLED TRIALS

18. Evaluate the comparative effectiveness of ERAS versus
standard care (SC) on various perioperative outcomes of
interest after cystectomy and urinary diversion.
META-ANALYSIS
SYSTEMATIC REVIEW

19. HYPOTHESIS
POOLED ANALYSIS WOULD FAVOR
ERAS FOR LENGTH OF STAY,
TIME-TO-BOWEL ACTIVITY,
COMPLICATIONS,
AND READMISSION RATES.

20. 2
Study aims
Literature search
Inclusion and exclusion criteria
Data extraction
Assessment of quality
Handling of missing variance estimates
Statistical analysis
E V I D E N C E A C Q U I S I T I O N
P A R T

21. PRISMA-P 2015
CHECKLIST
COCHRANE
HANDBOOK
Evaluate the comparative effectiveness of ERAS pathways versus SC in
reducing the length of stay, complications, readmission, and time-to-
bowel activity after cystectomy and urinary diversion.
STUDY
AIMS

22. WHAT IS
It uses explicit, systematic methods to minimize bias in the identification,
selection, synthesis, and summary of studies.
When done well, this provides reliable findings from which conclusions can
be drawn and decisions made.
SYSTEMATIC
REVIEWSC O L L AT E A L L R E L E VA N T E V I D E N C E S T H AT F I T S
P R E - S P E C I F I E D E L I G I B I L I T Y C R I T E R I A TO A N S W E R
A S P E C I F I C R E S E A R C H Q U E S T I O N

23. (a) A clearly stated set of objectives with an explicit, reproducible methodology
(b) A systematic search that attempts to identify all studies that would meet the eligibility
criteria
(c) An assessment of the validity of the findings of the included studies (e.g., assessment
of risk of bias and confidence in cumulative estimates)
(d) Systematic presentation, and synthesis, of the characteristics and findings of the
included studies
SYSTEMATIC
REVIEWS
K E Y C H A R A C T E R I S T I C S

24. WHY
Used to support the development of clinical practice guidelines and inform
clinical decision-making. Ideally, systematic reviews are based on pre-
defined eligibility criteria and conducted according to a pre-defined
methodological approach as outlined in an associated protocol.
SYSTEMATIC
REVIEWSR E F E R E N C E S TA N D A R D F O R S Y N T H E S I Z I N G E V I D E N C E
I N H E A LT H C A R E D U E TO I T S M E T H O D O L O G I C A L R I G O R

25. WHAT IS
By combining data from several studies, meta-analyses can provide more
precise estimates of the effects of health care than those derived from the
individual studies.
META-ANALYSIS
U S E O F S TAT I S T I C A L T E C H N I Q U E S TO C O M B I N E A N D
S U M M A R I Z E T H E R E S U LT S O F M U LT I P L E S T U D I E S

26. WHAT IS
The protocol details the rationale and a priori methodological and analytical
approach of the review.
PROTOCOL
A D O C U M E N T T H AT P R E S E N T S A N E X P L I C I T P L A N
F O R A S Y S T E M AT I C R E V I E W

27. WHY
Ensures that a systematic review is carefully planned and that what is
planned is explicitly documented before the review starts, thus promoting
consistent conduct by the review team, accountability, research
integrity, and transparency of the eventual completed review.
PROTOCOL
PREPARATIONR E D U C E A R B I T R A R I N E S S I N D E C I S I O N - M A K I N G W H E N
E X T R A C T I N G A N D U S I N G D ATA F R O M P R I M A RY R E S E A R C H ,
S I N C E P L A N N I N G P R O V I D E S A N O P P O RT U N I T Y F O R T H E
R E V I E W T E A M TO A N T I C I PAT E P O T E N T I A L P R O B L E M S

28. WHY
When clearly reported protocols are made available, they enable readers to
identify deviations from planned methods in completed reviews and
whether they bias the interpretation of a review results and conclusions.
PROTOCOL
PREPARATIONB I A S R E L AT E D TO T H E S E L E C T I V E R E P O RT I N G O F
O U T C O M E S H A S B E E N C H A R A C T E R I Z E D A S A S E R I O U S
P R O B L E M I N C L I N I C A L R E S E A R C H ,
I N C L U D I N G S Y S T E M AT I C R E V I E W S

29. PRISMA-P 2015
CHECKLIST
COCHRANE
HANDBOOK
Accordingly, this protocol is registered at the International Prospective
Register of Ongoing Systematic Reviews.
(registration number: CRD42016033882)
STUDY
AIMS

30. LITERATURE SEARCH-PAST 5 YR
E N G L I S H - L A N G U A G E
E L E C T R O N I C D ATA B A S E S
EMBASE
GOOGLE
SCHOLAR
WEB OF SCIENCE
MEDLINE
(PUBMED)
OBSERVATIONAL
STUDIES
AND
RANDOMIZED
CONTROLLED
TRIALS

31. LITERATURE SEARCH-PAST 5 YR
E N G L I S H - L A N G U A G E
E L E C T R O N I C D ATA B A S E S
AMERICAN
UROLOGICAL
ASSOCIATION
GREY
LITERATURE
EUROPEAN
UROLOGICAL
ASSOCIATION
COCHRANE
LIBRARY
OBSERVATIONAL
STUDIES
AND
RANDOMIZED
CONTROLLED
TRIALS

32. CYSTECTOMY
❖ THE LAST SEARCH WAS PERFORMED ON FEBRUARY 1, 2016
❖ SCANNED THE REFERENCE LISTS OF THE INCLUDED STUDIES OR RELEVANT REVIEWS
FOR ADDITIONAL CANDIDATE ARTICLES
ENHANCED RECOVERY
AFTER SURGERY
COLLABORATIVE
CARE PATHWAYS

33. TWOMEMBERS INDEPENDENTLY ASSESS
C
RITERIA
Inclusion and Exclusion

34. STUDIES COMPARING ERAS
WITH STANDARD
POSTOPERATIVE
PATHWAYS
AFTER CYSTECTOMY
INCLUSION CRITERIA
ERAS PROTOCOLS IF THEY HAD
STANDARDIZED PREOPERATIVE,
INTRAOPERATIVE, AND POSTOPERATIVE
PATHWAYS THAT INCLUDED
PATIENT EDUCATION,
GOAL-DIRECTED FLUID MANAGEMENT,
PREVENTION OF NAUSEA AND VOMITING,
EARLY AMBULATION,
EARLY ORAL NUTRITION,
AND EARLY HOSPITAL DISCHARGE
AT LEAST ONE OF
THE MAIN OUTCOMES
OF INTEREST
(READMISSION,
COMPLICATIONS,
TIME-TO-BOWEL FUNCTION,
OR LENGTH OF STAY)

35. No outcomes of interest were reported
or were impossible to calculate or extrapolate
1
The inclusion criteria were not met
EXCLUSION CRITERIA
2

36. Studies using robotic approaches to cystectomy
were allowed provided
the distribution of laparoscopic technology
was equal in both the ERAS and SC groups
EXCLUSION CRITERIA

37. E X T R A C T I O N
One investigator independently extracted data from the primary
texts, supplementary appendixes, and protocols using data
abstraction forms that contained fields for authors, publication year,
country, study design, matching factors, and outcomes of interest.
DATA

38. F A C T O R S
Age, proportion of men, body mass index, American Society of
Anesthesiologists score, clinical stage, diversion type, prior major
pelvic or abdominal surgery, and receipt of neoadjuvant chemotherapy
MATCH

39. O F I N T E R E S T
Readmission rates (30 d and 90 d), perioperative complication rates
(Grade 2 and Grade 3 according to the Clavien-Dindo classification),
length of stay, time-to-bowel movement, and analgesia requirements
OUTCOME

41. ❖ M.D.T. independently rated the level of evidence of the included studies according
to the criteria provided by the Oxford Centre for Evidence-Based Medicine.
❖ The methodological quality of the studies was assessed using the Newcastle-
Ottawa scale for observational comparative studies.
QUALITY
A S S E S S M E N T

42. Oxford Centre for Evidence-based Medicine –
Levels of Evidence (March 2009)

43. VARIANCE
E S T I M AT E S
M I S S I N G
❖ Continuous data as median and range or interquartile range, the means and
standard deviations were calculated using the method described by Wan et al.

44. VARIANCE
E S T I M AT E S
M I S S I N G
❖ Means and p values without standard deviations or ranges, the standard error
was estimated using the corresponding t value (as estimated from the p value
and degrees of freedom). The standard deviation was then calculated using the
standard error.

45. VARIANCE
E S T I M AT E S
M I S S I N G
❖ With missing p values, t values, confidence intervals, and standard errors, we
imputed the pooled standard deviation using the average of the standard
deviations across the other studies in the meta-analysis, as described by
Furukawa et al.

46. ANALYSIS
S TAT I S T I C A L
❖ The meta-analysis was performed using the metan package in Stata 14/MP.
❖ All statistical methods followed the principles outlined in the Cochrane Handbook
for Systematic Reviews of Interventions.

47. ANALYSIS
S TAT I S T I C A L
❖ The standardized mean difference (SMD) and risk ratios (RRs) were used to
compare continuous and dichotomous variables, respectively.
❖ For interpreting standardized mean differences: 0.2 represents a small effect, 0.5
represents a moderate effect, and 0.8 represents a large effect.

48. ANALYSIS
S TAT I S T I C A L
❖ The number needed to treat is computed using the inverse of the assumed control
risk multiplied by the RR subtracted from 1.
❖ All results were reported with 95% confidence intervals (CIs).

49. ANALYSIS
S TAT I S T I C A L
❖ Statistical heterogeneity between studies was assessed using the 𝛘2 test, with a
p value of less than 0.1 considered to indicate statistical significance, and
heterogeneity was quantified using the inconsistency (I2) statistic.

50. ANALYSIS
S TAT I S T I C A L
❖ A random-effects model was used for outcomes that displayed significant
heterogeneity with I2 values greater than 50%; otherwise, an inverse-weighted,
fixed-effects model was used.

51. ANALYSIS
S TAT I S T I C A L
❖ To test the impact of imputation on the study findings, a sensitivity analysis was
performed, which excluded the studies for which variance parameters had to be
imputed (three studies in total).

52. ANALYSIS
S TAT I S T I C A L
❖ Publication bias was assessed using contour-enhanced funnel plots.
❖ Because the visual interpretation of funnel plot asymmetry is inherently subjective,
we also formally tested funnel plot asymmetry using the Harbord modification of the
Egger test.

53. 3
Characteristics and quality of included studies
Readmissions
Complications
Length of stay and time-to-bowel activity
Publication bias and small-study effects
Sensitivity analysis
E V I D E N C E S Y N T H E S I S
P A R T

54. CHARACTERISTICS AND QUANTITY
The literature yielded 13 comparative studies that fulfilled the inclusion
criteria and were considered suitable for meta-analysis.
N = 1493
OF INCLUDED STUDIES,

55. 801
ERAS PARTICIPANTS
CONTROLS WHO RECEIVED SC
692

57. Overall, ERAS did not significantly reduce the likelihood of patients being
readmitted after cystectomy.
In raw terms, approximately 14.9% (59/396) of patients in the ERAS group
were readmitted within 90 d compared with 15.9% (60/376) of patients in
the SC group.
READMISSIONS ,

59. Overall, the complication rate favored the ERAS group.
In raw terms, approximately 39.6% (209/527) of the ERAS patients had a
complication compared with 51.5% (237/461) of patients in the SC group.
COMPLICATIONS ,

61. The number needed to treat to prevent one complication is
approximately 14.
COMPLICATIONS ,

62. When stratified by the Clavien-Dindo classification, most of the variation between
groups was attributable to a reduction in the risk of low-grade complications
(Clavien-Dindo Grade I or II) among ERAS participants.
COMPLICATIONS ,

63. The 90-d mortality rate did not differ between the groups.
(RR: 0.97, 95% CI: 0.36–2.62, p = 0.96, I2 = 0%)
COMPLICATIONS ,

64. Pooled data from 12 studies that assessed length of stay in 1381 patients
strongly favored the ERAS group.
(SMD: 0.87, 95% CI: 1.31 to 0.42, p = 0.001, I2 = 92.8%)
LENGTH OF STAY ,

66. The estimated mean difference between groups for length of stay was
approximately 5.4 d in favor of ERAS.
LENGTH OF STAY ,

67. Pooled data from seven studies assessing the time to return of bowel
function (five assessing time-to-bowel movement and two assessing time to
flatus) in 554 patients favored a faster return of bowel function among
the ERAS participants.
(SMD: 1.02, 95% CI: 1.69 to 0.34, p = 0.003, I2 = 92.2%)
TIME-TO-BOWEL ACTIVITY ,

69. The estimated mean difference in return of bowel function between groups
was 1.1 d in favor of ERAS.
TIME-TO-BOWEL ACTIVITY ,

70. PUBLICATION BIAS AND
Funnel plots were used to investigate the presence of small-study effects
and publication bias.
SMALL-STUDY EFFECTS ,

71. S
SMALL-STUDY EFFECTS
A G E N E R I C T E R M F O R T H E
P H E N O M E N O N T H A T S M A L L E R S T U D I E S
S O M E T I M E S S H O W D I F F E R E N T , O F T E N
L A R G E R , T R E A T M E N T E F F E C T S T H A N
L A R G E O N E S .
M A L L S T U D Y

72. S
SMALL-STUDY EFFECTS
O N E P O S S I B L E , P R O B A B L Y T H E M O S T
W E L L - K N O W N , R E A S O N I S P U B L I C A T I O N
B I A S .
T H I S I S S A I D T O O C C U R W H E N T H E
C H A N C E O F A S M A L L E R S T U D Y B E I N G
P U B L I S H E D I S I N C R E A S E D I F I T S H O W S
A S T R O N G E R E F F E C T .
M A L L S T U D Y

73. S
SMALL-STUDY EFFECTS
T H I S C A N H A P P E N F O R A N U M B E R O F
R E A S O N S , F O R E X A M P L E A U T H O R S M A Y
B E M O R E L I K E L Y T O S U B M I T S T U D I E S
W I T H “ S I G N I F I C A N T ” R E S U L T S F O R
P U B L I C A T I O N O R J O U R N A L S M A Y B E
M O R E L I K E L Y T O P U B L I S H S M A L L E R
S T U D I E S I F T H E Y H A V E “ S I G N I F I C A N T ”
R E S U L T S .
M A L L S T U D Y

74. S
SMALL-STUDY EFFECTS
I F T H I S O C C U R S , I T I N T U R N B I A S E S
T H E R E S U L T S O F M E T A - A N A L Y S E S A N D
S Y S T E M A T I C R E V I E W S .
M A L L S T U D Y

76. PUBLICATION BIAS AND
The Harbord modification of the Egger test provided evidence that the
assessment of complications may be confounded by publication bias.
(p = 0.046)
SMALL-STUDY EFFECTS ,

77. PUBLICATION BIAS AND
Minimal bias was detected for readmissions (p = 0.23), length of stay (p =
0.52), and time-to-bowel activity (p = 0.91).
SMALL-STUDY EFFECTS ,

78. Because the standard deviations had to be imputed for select studies
involving the outcomes of interest (length of stay and time-to-bowel
movement), we repeated the analysis excluding the three studies for these
outcomes of interest.
SENSITIVITY ANALYSIS ,

79. We did not find any significant qualitative difference when this analysis was
compared with our main analysis.
SENSITIVITY ANALYSIS ,

80. P A R T
4
C O N C L U S I O N S

81. PRINCIPLE FINDING
The implementation of standardized, perioperative pathways for
cystectomy patients reduces the length of the index hospitalization,
lowers the rate of low-grade complications, and improves the time-to-
bowel function.
No difference in overall readmission rates was noted.

82. I M P O R TA N T C L I N I C A L I M P L I C AT I O N S
L E N D F U R T H E R E V I D E N C E F O R T H E I M P L E M E N TAT I O N O F
S TA N D A R D I Z E D , E V I D E N C E - B A S E D P E R I O P E R AT I V E
P R O T O C O L S I N C E N T E R S N O T P R E S E N T LY U S I N G T H E M .
EVIDENCE

83. THEORETICAL
REASONS
MANY OF THE PRINCIPLES
OF ERAS
HAVE A PHYSIOLOGIC BASIS
Why ERAS protocols would improve perioperative outcomes
ERAS PATHWAYS ARE ADAPTIVE, EVIDENCE-BASED
RESPONSES TO SPECIFIC PROBLEMS AND
CARE NEEDS AT THE ORGANIZATIONAL LEVEL
STANDARDIZED PROTOCOLS HAVE THE
POTENTIAL ADVANTAGE OF REDUCING
VARIATION IN CARE, EVEN IF THE
PROTOCOLS DIFFER

84. ISSUE
The uncertainty about which pathway is best.
Each study included in this meta-analysis used a perioperative pathway that is
distinct in some way from all pathways used in the other studies.
Can these data really be synthesized and can meaningful results truly be gleaned
from the pooled estimates?

85. EXPLANATION
The aim of this study was not to suggest which pathway was best or which
elements should be universally adopted.
Rather, the purpose of this meta-analysis was to determine whether these
pathways have an effect at all.

86. EXPLANATION
The differences in the pathways notwithstanding, this study demonstrates that
merely adopting a standardized, multimodal, interdisciplinary protocol for the
perioperative management of cystectomy patients may be as important to
improving perioperative outcomes as any individual element by itself.

87. The main limitation is that all of the studies included were
observational studies, and most used historical controls.
This almost certainly biased the pooled estimates in favor of
ERAS.
There is no question that in the current era providers have
become more conscious of the length of stay, complications,
and readmission rates irrespective of perioperative pathways.
L I M I TAT I O N
O B S E R VAT I O N A L S T U D I E S

88. A randomized study or a retrospective study using a
difference-in-differences approach would more
accurately quantify the effect of ERAS on
perioperative outcomes of interest.
Although one randomized trial was identified, it did
not evaluate any of the primary outcomes of interest.
L I M I TAT I O N
O B S E R VAT I O N A L S T U D I E S

89. Nevertheless, there were clear and meaningful effects
of ERAS pathways that emerged after the pooling of
the data, which are compelling and are consistent with
what has been reported in colorectal literature.
L I M I TAT I O N
O B S E R VAT I O N A L S T U D I E S

90. For some of the outcomes of interest, fewer than 10
studies have been published, which results in a low
test power for assessing funnel plot asymmetry.
However, we also interpreted the test results in the
context of visual inspection of the funnel plots.
L I M I TAT I O N
L O W T E S T P O W E R

91. No evaluation regarding costs and patient-reported
outcomes, such as quality of life, mainly because of
the relative absence of these data in the cystectomy
population.
L I M I TAT I O N
N O E VA L U AT I O N

92. They believe these data are
clinically relevant for quality
improvement efforts for
organizations that care for
cystectomy patients.
NEVERTHELESS…

93. The data support the
development of integrated,
multidisciplinary clinical
pathways in an effort to
improve patient outcomes,
reduce errors, and increase
patient and provider
satisfaction.
NEVERTHELESS…

94. Although a randomized trial
may not be feasible because of
the lack of clinical equipoise in
this setting, this study
substantially improves the
evidence for ERAS pathways
in the cystectomy population.
NEVERTHELESS…

95. CYSTECTOMY
URINARY DIVERSION
ERAS PATHWAYS
REDUCE THE LENGTH OF THE INDEX HOSPITALIZATION, THE TIME TO
RECOVERY OF BOWEL FUNCTION, AND COMPLICATIONS.
THESE DATA HAVE IMPORTANT CLINICAL IMPLICATIONS AND SHOULD
LEND FURTHER EVIDENCE FOR THE IMPLEMENTATION OF
STANDARDIZED, EVIDENCE-BASED PERIOPERATIVE PROTOCOLS IN
CENTERS NOT PRESENTLY USING THEM.

96. THANKS
F O R Y O U R L I S T E N I N G