Recombinant Activated Protein C in ScotlandSICSAG Trainee Sprint Audit

How we use itWhat we think about it(not going to get into should we use it!)

Alex Puxty SpR

OUTLINE

•Background▫The PROWESS trial▫Controversies

•The audit-▫Objectives▫Methods▫Results▫Conclusions

BACKGROUND

• PROWESS study published in 2001

• FDA approval in early 2002

• European licence six months later

• Adopted into both Surviving sepsis and NICE guidelines (2004)

PROWESS

•Randomized, double blind trial

•164 centres (none in UK)

•1690 patients

•Severe sepsis of less than 24hrs duration

PROWESS-HEADLINE RESULTS

•19.4% RRR of death (6.1% ARR); p=0.005

•Trend towards more bleeding (3.5% Vs 2%; p=0.06)

PROWESS-CONTROVERSIES

GUIDELINES•NICE 2004-

The intervention is a cost-effective option for use in severe sepsis whose risk of death was increased due to multiple organ failure

•SURVIVING SEPSIS 2004rhAPC is recommended in patients at highrisk of death (APACHE II ≥ 25, sepsis-

inducedmultiple organ failure, septic shock, orsepsis-induced acute respiratory distresssyndrome [ARDS]) and with no absolutecontraindication related to bleeding risk orrelative contraindication that outweighsthe potential benefit of rhAPC

GUIDELINES

•SURVIVING SEPSIS 2008

Consider rhAPC in adult patients with sepsis induced organ dysfunction with clinical assessment of high risk of death (typically APACHE II ≥25 or multiple organ failure) if there are no contra-indications

RESOLVE AND ADDRESS

•RESOLVE Not a mortality study Stopped early as little chance of reaching

efficacy endpoint

•ADDRESS Stopped after 2nd interim analysis <5% chance of reaching endpoint of significant

mortality reduction

COCHRANE 2008

This review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. Additionally, APC seems to be associated with a higher risk of bleeding. Unless additional RCTs provide evidence of a treatment effect, policy-makers, clinicians and academics should not promote the use of APC.

The Audit ItselfWhat is the trainee Sprint audit again?

SICSAG TRAINEE SPRINT AUDIT•3RD audit carried out

•Previously audit of thromboprophylaxis

•R+R audit

GETTING STARTED• Proposal to SICSAG committee

• Three regional coordinators

• Further recruitment to total 24 data collectors

• Protocol written

• Database formed

• Pilot

OBJECTIVES

•To determine the pattern of usage of rAPC in Scottish ICU’s

•Compare this to published guidelines

•Determine consultants attitudes towards rAPC

METHODS

•Two parts:

2 week data collection

Questionnaire to all consultants with ICU sessions

METHODS

•Two parts:

2 week data collection

Questionnaire to all consultants with ICU sessions

DATA COLLECTION

•All patients admitted with severe sepsis

•2 weeks beginning second week of January 2008

•Followed up for 72hrs split into 4 time periods

DATA COLLECTION

•Demographics•Source sepsis•Organ failures•APACHE II score•Contra-indications•Reasons recorded for not prescribing (if

needed)•Inotropes (converted to mcg/kg/min)•INR

DATA COLLECTION

SICSAG provided:

Unit and hospital LOS

Predicted mortality

Mortality

RESULTS

•97 patients

•49 (51.5%) male

•Mean age 59.8yrs

•Median APACHE II -25

RESULTS

•Overall 66 of 97 had outcome data

•In these, mean predicted mortality was 45.9%

•Actual mortality was 36.3% (SMR 0.79)

APACHE II SCORES RECORDED

DIVIDING THE PATIENTS

•Stratified-split into 3 categories

•Excluded all with contra-indications

•Split into NICE and SSC guidelines

ORGAN FAILURE CRITERIA

ORGAN FAILURE CRITERIA

PERCENTAGE OF PRESCRIPTIONS “MISSED”-

ORGAN CRITERIA

APACHE II CRITERIA

APACHE II CRITERIA

PERCENTAGE OF PRESCRIPTIONS “MISSED”-

APACHE II CRITERIA

CONTRA-INDICATIONS

WHO DID GET rAPC?

•Median APACHE II-33

•All on inotropes

•No age difference

•Median organ failures -4

THOSE WHO GOT rAPC

CONCLUSIONS OF DATA COLLECTION•No one got rAPC who did not qualify by

either criteria

•Contra-indications were common (33%)

•rAPC seemed to be used only in some of the sicker patients

CONCLUSIONS OF DATA COLLECTIONUsing organ failure criteria:

• Between 61% and 79% “missed” prescription of rAPC

Using APACHE II criteria:

• Between 50% and 71% “missed” prescription of rAPC

THE QUESTIONNAIREDONT WORRY, WE’RE MORE THAN HALF WAY!

METHODS

•Direct contact!

•All consultants with daytime ICU sessions

•After data collection complete

•125/162 returns=77% response rate

DO YOU BELIEVE THE EVIDENCE IN SUPPORT OF rAPC

Organ/System Failure Median Score

CVS 1

Respiratory 3

Renal 3

Metabolic 4

Haematological 5

SCENARIO

You have a patient with chest sepsis with a reduced blood pressure and acute kidney injury. You use all standard therapies over the first day of treatment.The inotrope requirement reduces and the ventilation improves slightly. THEY STILL MEET CRITERIA FOR rAPC.

CLINICAL SCENARIO-WOULD YOU PRESCRIBE?

CONCLUSIONS FROM QUESTIONNAIRE•In no unit did all consultants say they did

not use rAPC

•Despite this, there remains significant concern regarding the current evidence

•Cardiovascular failure is generally felt to be the most important “system”

•Most consultants would use discretion in prescription

RECOMMENDATIONS

•Be aware that more patients are qualifying for treatment than are currently being considered

•Record decisions in notes

•Ideally single guideline

ACKNOWLEDGEMENTS• SICSAG (in particular Angela Kellacher, Catriona Haddow,

Sarah Ramsay and Brian Cook) • Paul McConnell, Simon Crawley, Simon McAree

Lia Paton Jane Wilkinson Laura Robertson

Tim Geary Catriona Chalmers Ewan McMillan

Dave Griffiths Claire Tordoff Richard Appleton

Craig Beattie Kirankumar Sachane Andrew Goddard

Jonathan Antrobus Gordon Houston Andrew Clarkin

Fahmi Faraz Megan Dale Raj Najeurs

Euan McGregor Prit Anand Singh Myra McAdam

Bhushan Joshi John Glen