Transcript Recombinant Activated Protein C in Scotland SICSAG Trainee

Recombinant Activated Protein C in
Scotland
SICSAG Trainee Sprint Audit
How we use it
What 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
• Post Hoc sub-group analysis
• Protocol changes▫ Co-morbidites
▫ Cell line production
•
Mortality reduction greater after the change
• FDA and Eli Lily tested both cell lines
GUIDELINES
• NICE 2004The intervention is a cost-effective option for use in
severe sepsis whose risk of death was increased due to
multiple organ failure
• SURVIVING SEPSIS 2004
rhAPC is recommended in patients at high
risk of death (APACHE II ≥ 25, sepsis-induced
multiple organ failure, septic shock, or
sepsis-induced acute respiratory distress
syndrome [ARDS]) and with no absolute
contraindication related to bleeding risk or
relative contraindication that outweighs
the 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 Itself
What 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
50
45
40
APACHE II
35
30
25
20
15
10
5
0
patients
DIVIDING THE PATIENTS
• Stratified-split into 3 categories
• Excluded all with contra-indications
• Split into NICE and SSC guidelines
ORGAN FAILURE CRITERIA
97 patients
16 patients never
“triggered”
81 patients
with 2 or more
organ failures
31contraindications
9 patients
received rAPC
41 patients
“missed”
ORGAN FAILURE CRITERIA
41 patients
4 discharged
in the 72hrs
15 improved
but still met
criteria
8 improved
and no longer
met criteria
2 died
12 had no
improvement
%
PERCENTAGE OF PRESCRIPTIONS
“MISSED”-ORGAN CRITERIA
80
70
60
50
40
30
20
10
0
76
79
61
exclude any
improvement
exclude those
who no longer
qualified
exclude no one
APACHE II CRITERIA
97 PATIENTS
20 patients
had contraindications
48 met
criteria
20 patients
“missed”
49 patients
never
“triggered”
8 patients
received rAPC
APACHE II CRITERIA
20 patients
8 had no
improvement
8 improved
but still
qualified
2 died
2 improved
and no longer
qualified
%
PERCENTAGE OF PRESCRIPTIONS
“MISSED”-APACHE II CRITERIA
80
70
60
50
40
30
20
10
0
71
50
exclude any
improvement
56
exclude those
who no longer
qualified
exclude no one
CONTRA-INDICATIONS
9
8
number of patients with reason
7
6
5
4
3
2
1
0
MOF from
other
epidural
recent Sx
Neuro Sx
Futility
Bleeding
diathesis
Severe liver
disease
low
platelets
Active
bleeding
outside
time limit
unclear Dx
WHO DID GET rAPC?
• Median APACHE II-33
• All on inotropes
• No age difference
• Median organ failures -4
NO. OF INOTROPES PATIENTS
RECEIVED
2
2
1.8
1.8
1.6
1.4
1.24
1
1.2
1
0.8
0.6
0.4
0.2
0
mean
median
no of inotropes in
those prescribed
no. Inotropes in those
not prescribed
NORADRENALINE DOSES
0.5
0.45
0.4
0.46
0.42
0.375
mcg/kg/min
0.35
0.3
0.2
0.25
0.2
0.15
0.1
0.05
0
dose at prescription
dose in those not being
prescribed
mean
median
THOSE WHO GOT rAPC
• 8 of 9 survived to discharge from hospital
• 2 of these had the drug discontinued before
completion
▫ 1 for bleeding
▫ 1 as improved
• Mean unit LOS 17 days (range 6-26)
• Mean hospital LOS 39 days (range 18-65)
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 COLLECTION
Using organ failure criteria:
• Between 61% and 79% “missed” prescription of rAPC
Using APACHE II criteria:
• Between 50% and 71% “missed” prescription of rAPC
THE QUESTIONNAIRE
DONT 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
Does your Unit use
rAPC?
Reasons for not Using
rAPC
Yes
13
No
experience
1
4
no
111
Dont
know
3
Dont
believe
evidence
2
6
Too many
complicatio
ns
Combinatio
n of factors
Criteria for using rAPC
39
8
2 ORGAN +
APACHE >25
2 organ
failure only
56
Others
Typical Organ Failure
Requirement for rAPC
prescription
46
1
2 Organ
Failure
51
3 Organ
Failure
4 Organ
Failure
DO YOU BELIEVE THE EVIDENCE IN
SUPPORT OF rAPC
70
65
60
50
38
40
30
19
20
10
0
Equivocal
No
Yes
Ranking of Organ Failure Influence on rAPC
prescribing decisions
Number of Responses
80
70
60
CVS
50
RESP
40
30
RENAL
20
10
METABOLIC
0
1
2
3
4
Organ Failure Ranking
5
BLOOD
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?
80
70
60
50
40
30
20
10
0
Yes
No
Unsure
More
information
required
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