E N H A N C E D R E C O V E R Y PAT H W AY S V E R S U SS TA N D A R D C A R EA 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, CHENJournal Club, KFSYSCC, 2017/02/16

PART01Objective

PART02Evidence Acquisition

PART03Evidence Synthesis

PART04Conclusions

CONTENTS

PART

1To 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

About the ERAS, and the context of the present study

N T R O D U C T I O NI

MULTIMODALSTANDARDIZED

INTERDISCIPLINARY

ERASA B O U T

PHYSIOLOGICALPSYCHOLOGICAL

RESPONSES

MODIFY

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?

PREOPERATIVECONSELLING

1 2 3 4

OPTIMIZATIONOF NUTRITION

STANDARDIZEDANALGESIC / ANESTHETICREGIMENS

EARLYMOBILIZATION

K E Y E L E M E N T S

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

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 breakfastAdmit to hospital

Unrestricted clear fluidsRefer to dietician

Assess social circumstances and refer if needed

- 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

- 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

DAY 11-14

Continue as previous and schedule for return to home

BACKGROUNDCYSTECTOMY WITH URINARY DIVERSION

AIM OF ERAS

IMPROVESURGICAL OUTCOMESBYREDUCING VARIATIONINPERIOPERATIVEBEST PRACTICES

REDUCE THE LENGTH OF STAY?SHORTEN THE TIME TO RECOVERY OF BOWEL ACTIVITY?LOWER THE RATES OF READMISSION

VARIABILITY IN STUDY RESULTSABSENCE OF EXPERIMENTAL DATAFROM RANDOMIZED, CONTROLLED TRIALS

Evaluate the comparative effectiveness of ERAS versus standard care (SC) on various perioperative outcomes of

interest after cystectomy and urinary diversion.

META-ANALYSISSYSTEMATIC REVIEW

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

2

Study aimsLiterature search

Inclusion and exclusion criteriaData extraction

Assessment of qualityHandling of missing variance estimates

Statistical analysis

E V I D E N C E A C Q U I S I T I O NP A R T

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.

STUDYAIMS

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.

SYSTEMATICREVIEWSC 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 T O 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

(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

SYSTEMATICREVIEWSK E Y C H A R A C T E R I S T I C S

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.

SYSTEMATICREVIEWSR 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 EI N H E A LT H C A R E D U E T O I T S M E T H O D O L O G I C A L R I G O R

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-ANALYSISU S E O F S TAT I S T I C A L T E C H N I Q U E S T O 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

WHAT IS

The protocol details the rationale and a priori methodological and analytical approach of the review.

PROTOCOLA 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

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.

PROTOCOLPREPARATION

R 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 R Y 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 R T U N I T Y F O R T H E R E V I E W T E A M T O 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

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.

PROTOCOLPREPARATIONB I A S R E L AT E D T O T H E S E L E C T I V E R E P O R T I N G O FO 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

PRISMA-P 2015 CHECKLIST

COCHRANE HANDBOOK

Accordingly, this protocol is registered at the International Prospective Register of Ongoing Systematic Reviews.(registration number: CRD42016033882)

STUDYAIMS

LITERATURE SEARCH-PAST 5 YRE N G L I S H - L A N G U A G EE L E C T R O N I C D ATA B A S E S

EMBASE

GOOGLE SCHOLAR

WEB OF SCIENCEMEDLINE (PUBMED)

OBSERVATIONALSTUDIES

AND

RANDOMIZEDCONTROLLED

TRIALS

LITERATURE SEARCH-PAST 5 YRE N G L I S H - L A N G U A G EE 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

OBSERVATIONALSTUDIES

AND

RANDOMIZEDCONTROLLED

TRIALS

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 RECOVERYAFTER SURGERY

COLLABORATIVECARE PATHWAYS

TWO MEMBERS INDEPENDENTLY ASSESS

CRITER

IAInclusion and Exclusion

STUDIES COMPARING ERASWITH STANDARDPOSTOPERATIVE

PATHWAYSAFTER CYSTECTOMY

INCLUSION CRITERIA

ERAS PROTOCOLS IF THEY HADSTANDARDIZED PREOPERATIVE,

INTRAOPERATIVE, AND POSTOPERATIVEPATHWAYS 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 OFTHE MAIN OUTCOMES

OF INTEREST(READMISSION,

COMPLICATIONS,TIME-TO-BOWEL FUNCTION,

OR LENGTH OF STAY)

No outcomes of interest were reportedor were impossible to calculate or extrapolate

1The inclusion criteria were not met

EXCLUSION CRITERIA2

Studies using robotic approaches to cystectomywere allowed provided

the distribution of laparoscopic technologywas equal in both the ERAS and SC groups

EXCLUSION CRITERIA

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

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

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

❖ 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.

QUALITYA S S E S S M E N T

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

VARIANCEE S T I M A T 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.

VARIANCEE S T I M A T 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.

VARIANCEE S T I M A T 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.

ANALYSISS T A T 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.

ANALYSISS T A T 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.

ANALYSISS T A T 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).

ANALYSISS T A T 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.

ANALYSISS T A T 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.

ANALYSISS T A T 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).

ANALYSISS T A T 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.

3Characteristics 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 SP A R T

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,

801

ERAS PARTICIPANTS

CONTROLS WHO RECEIVED SC

692

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 ,

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 ,

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

COMPLICATIONS ,

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 ,

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 ,

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 ,

The estimated mean difference between groups for length of stay was approximately 5.4 d in favor of ERAS.

LENGTH OF STAY ,

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 ,

The estimated mean difference in return of bowel function between groups was 1.1 d in favor of ERAS.

TIME-TO-BOWEL ACTIVITY ,

PUBLICATION BIAS AND

Funnel plots were used to investigate the presence of small-study effects and publication bias.

SMALL-STUDY EFFECTS ,

SSMALL-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

SSMALL-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

SSMALL-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

SSMALL-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

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 ,

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 ,

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 ,

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

SENSITIVITY ANALYSIS ,

P A R T

4

C O N C L U S I O N S

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.

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 SL 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 .

EVIDEN

CE

THEORETICALREASONS

MANY OF THE PRINCIPLESOF 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

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?

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.

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.

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 T A T I O NO B S E R VAT I O N A L S T U D I E S

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 T A T I O NO B S E R VAT I O N A L S T U D I E S

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 T A T I O NO B S E R VAT I O N A L S T U D I E S

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 T A T I O NL O W T E S T P O W E R

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 T A T I O NN O E VA L U AT I O N

They believe these data are clinically relevant for quality

improvement efforts for organizations that care for

cystectomy patients.

NEVERTHELESS…

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…

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…

CYSTECTOMYURINARY DIVERSION

ERAS PATHWAYSREDUCE 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.

T H A N K SF O R Y O U R L I S T E N I N G