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he Citrate Story David Gattas gives an update on today's go-to anti-coagulant for renal replacement therapy: Citrate David is a key figure in the ANZICS CTG, with a growing list of publications and was involved in the RENAL and POST-RENAL studies. Long-Term Survival and Dialysis Dependency Following Acute Kidney Injury in Intensive Care: Extended Follow-up of a Randomized Controlled Trial is available free. This talk was recorded live at an ICN NSW / ANZICS meeting in September 2014.
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CITRATE
in
CRRTDavid Gattas
david.gattas@sydney.edu.au
@dgattas
CRRT: What are you trying
to ACHIEVE?
Solute control?
Fluid removal?
Improve a life?
Save a life?
This is a TECHNICAL taskRequiring technical SKILLS
PATIENTS ONLY LIKE
INTENSIVISTS WHO
HAVE GREAT CRRT
FILTER LIFE SKILLS
The Heparin Citrate (THC) Study
David GattasMBBS MMed (ClinEpi), FRACP FCICM
Senior Staff Specialist, Intensive Care, Royal Prince Alfred Hospital
Clinical Associate Professor, Sydney Medical School, University of Sydney
david.gattas@sydney.edu.au
A randomised controlled study comparing the effect of two
different anticoagulation regimens on filter life during
Continuous Renal Replacement Therapy (CRRT)
ACTRN 12609001079235
Trial Management, Grant Applicants
Rinaldo BellomoCelia BradfordDavid GattasDorrilyn Rajbhandari
Statistician
Serigne Lo – George Institute
Funding
Funded 2010, AUD $55 000
With great THANKS to
SLHD (RPAH Zone) HREC Approval: X09-0068 & HREC/09/RPAH/98
The Heparin Citrate (THC) Study
7 TRIAL SITES
Auckland City (NZ)
Shay McGuinness, Rachael Parke, Eileen Gilder
Austin (VIC)
Rinaldo Bellomo, Glenn Eastwood
Dandenong (VIC)
Sanjiv Vij, Katherine Shepherd, Bridget O’Bree
Frankston (VIC)
John Botha, Sharon Allsop, David Lewis
Monash (VIC)
Craig Walker, Pauline Galt, Tammy Lamac
Royal North Shore (NSW)
Celia Bradford, Anne O’Connor
Royal Prince Alfred (NSW)
David Gattas, Dorrilyn Rajbhandari, Heidi Buhr
AIM
To test the hypothesis that
regional citrate anticoagulation
is more effective than
regional heparin/protamine
anticoagulation
at maintaining functional filter lifein patients receiving CRRT
The Heparin Citrate Study ACTRN 12609001079235
INCLUSION
Commencing CRRT for
acute renal failure
Suitable for intervention or
control
Equipoise
Consent (prior or delayed)
At least 1 of: K>6.5, pH<7.2,
urea>25, creatinine >300,
oedema
Age <18y
Expected <24h in ICU
Contraindication to
intervention or control (eg
liver, H.I.T)
Expected difficulty adhering
to allocated group
EXCLUSION
The Heparin Citrate Study ACTRN 12609001079235
DESIGN
Randomised controlled trial
SETTING
SAMPLE SIZE: 220
Seven ICUs in Australia and NZ
2 in NSW, 4 in VIC, 1 NZ
Tertiary, metropolitan
The Heparin Citrate Study ACTRN 12609001079235
Pilot sample suggested approx. 18h v 14h was
plausible. At least 100 in each group, plus 10%
loss. No. of filters was unknown but expected to
be >>220
INTERVENTION
Regional citrate
anticoagulation
Regional
heparin/protamine
anticoagulation
CONTROL
The Heparin Citrate Study ACTRN 12609001079235
CRRT CIRCUIT ANTICOAGULATION
Between Sites: Different hardware, modalities, protocols
Within Sites: Same hardware, modality. Same/v similar
starting blood flow and fluid flow rates
Unblinded (statistician was blinded)
PRIMARY OUTCOME
Functional filter life
transmembrane pressure >300mmHg
visible clot obstructing flow / blood pump
other reason (free text)
Measured in time to clotting event (hours)
All free text reasons for stopping were adjudicated by 2 independent, blinded intensivists, and any disagreements resolved by consensus
Deemed by consensus: clotted, didn’t clot, or unsure
The Heparin Citrate Study ACTRN 12609001079235
SECONDARY OUTCOMES
1. Cytokines
Interleukins: IL-6, IL-8, IL-10
at t=0h, and t=48h post-randomisation
collected at RPA and Austin only
2. Red cells transfused
3. Duration of CRRT
4. ICU length of stay
5. Mortality: ICU, hospital
The Heparin Citrate Study ACTRN 12609001079235
STATISTICS – FILTER LIFEfor Repeated Event Survival Data
Clotted filters only – compare median filter life
Include all filters
Expect filter life heterogeneity between
individuals (and correlation within individuals)
Event dependence: One clotted filter may
make the next clotted filter more or less
likely
FRAILTY / RANDOM EFFECTS MODEL
- a variant of Cox proportional hazard regression
Box-Steffenheiser Statist Med 2006; 25: 3518
RESULTSFlow Diagram
The Heparin Citrate Study ACTRN 12609001079235
Recruiting:Jan 2010 - Jan 2013
RESULTSFlow Diagram
The Heparin Citrate Study ACTRN 12609001079235 100% of patients followed up for hospital mortality
RESULTSNumber of Filters from Each Patient
The Heparin Citrate Study ACTRN 12609001079235
204 patients (of 212 randomised)
contributed at least 1 study filter
Median 2 filters [IQR1-5.8]
Maximum 24 filters from 1 subject
RESULTSBaseline Characteristics – basic demographics
The Heparin Citrate Study ACTRN 12609001079235
Table. Baseline characteristics of the intervention and control group
Citrate (N=105) Heparin/protamine (N=107)
Age (y) 66.4 (14.3) 66.8 (14.9)
Male gender - no./total (%) 74/105 (71) 72/107 (67)
Weight
Measured (vs estimated) - no./total (%) 46/105 (44) 50/107 (47)
Weight (kg) 85.0 (20.6) 84.3 (22.9)
Source of admission to ICU - no./total (%)
Emergency department 24/105 (22.9) 38/107 (35.5)
Hospital ward 27/105 (25.7) 19/107 (17.8)
Operating theatre - elective 31/105 (29.5) 33/107 (30.8)
Operating theatre - emergency 4/105 (3.8) 3/107 (2.8)
Transfer from another hospital 4/105 (3.8) 6/107 (5.6)
Transfer from other ICU 9/105 (8.6) 6/107 (5.6)
Not available 6/105 (5.7) 2/107 (1.9)
Groups were well matched for age and gender
Control group had more patients from Emergency Dept
RESULTSBaseline Characteristics – diagnosis and severity
The Heparin Citrate Study ACTRN 12609001079235
Table. Baseline characteristics of the intervention and control group
Citrate (N=105) Heparin/protamine (N=107)
~ 12% cardiac surgery, ~8 %septic shock,
well matched groups including severity of illness
APACHE III Diagnostic Group - no./total (%)
Coronary artery bypass grafts 14/105 (13.3) 13/107 (12.1)
Renal disorders 10/105 (9.5) 7/107 (6.5)
Sepsis with shock, non-urinary 8/105 (7.6) 7/107 (6.5)
Other respiratory diseases 6/105 (5.7) 7/107 (6.5)
Valvular heart surgery 5/105 (4.8) 6/107 (5.6)
Other 62/105 (59.0) 67/107 (62.6)
APACHE II score - mean(SD) 25.6 (7.6) 25.0 (6.9)
Meeting criteria for severe sepsis - no./total (%) 45/105 (42.9) 32/107 (29.9)
SOFA: patients scoring 3+ at time of randomisation, no./total (%)
Renal 45/101 (44.5) 51/106 (48.1)
Cardiovascular 69/101 (68.3) 68/106 (64.2)
Respiratory 46/101 (45.5) 51/106 (48.1)
Coagulation 5/101 (5.0) 3/106 (2.8)
Liver 3/101 (3.0) 7/106 (6.6)
RESULTSBaseline Characteristics – vent, inotrope, labs
The Heparin Citrate Study ACTRN 12609001079235
Table. Baseline characteristics of the intervention and control group
Citrate (N=105) Heparin/protamine (N=107)
~73% patients ventilated, ~67% inotropes
Well matched at baseline for renal and haematological parameters
Mechanically ventilated - no./total (%) 77/105 (73.3) 75/107 (73.3)
Receiving inotropes - no./total (%) 74/105 (68.4) 71/107 (66.4)
Renal parameters - mean (SD)
Urea (mmol/L) 21.9 (13.3) 23.4 (13.8)
Creatinine (µmol/L) 309 (157) 322 (177)
Phosphate (mmol/L) 2.02 (0.83) 1.94 (0.94)
Urine output in 6h prior to randomisation (mL) 170 (262) 190 (222)
Haematological parameters - mean (SD)
Haemoglobin (g/L) 98.0 (16.6) 98.3 (26.2)
Platelet count (x10^9/L) 209 (146) 215 (143)
INR 1.5 (1.2) 1.4 (0.52)
APTT (s) 40 (18) 40 (14)
RESULTSPrimary Outcome
The Heparin Citrate Study ACTRN 12609001079235
Frailty Model Analysis: Hazard Ratios for FilterGroup
Description Point Estimate 95% Wald Confidence Limits
FilterGroup Hep/Prot vs Citr 2.029 1.359 3.028
Analysis of Maximum Likelihood Estimates
Parameter DF Parameter
Estimate Standard
Error Chi-Square Pr > ChiSq Hazard
Ratio Label
FilterGroup Hep/Prot 1 0.70736 0.20429 11.9888 0.0005 2.029 FilterGroup 0
The hazard ratio for a filter experiencing clotting in the
heparin/protamine group (compared to citrate) was
2.03 (95% CI 1.36-3.03, p<0.005)
Filters in the citrate group are half as likely to clot
Cox model with random effect by subject
RESULTSPrimary Outcome
The Heparin Citrate Study ACTRN 12609001079235 • Includes the first filter in each patient ONLY
Citrate median 39h (100 filters*)
vs
Hep/prot median 22.8h (104 filters*)
Log rank p= 0.0037
RESULTSNumber of Filters, Duration of CRRT
The Heparin Citrate Study ACTRN 12609001079235 * filter outcome adjudicated by 2 independent intensivists
Regional citrate anticoagulation was associated with
use of fewer filters, less clotted filters and
longer cumulative duration of CRRT
Number of filters included in the study*
CitrateHeparin/
protamineTotal
Clotted 226 310 536
Didn't Clot 127 112 239
Unclear 37 45 82
TOTAL 390 467 857
Duration of CRRT (hours) 8281 8015 16296
RESULTSClotted Filters Only
The Heparin Citrate Study ACTRN 12609001079235
Citrate median 16.5h (226 filters)
vs
Hep/prot median 11.8h (310 filters)
(Mann-Whitney U) p<0.0001
RESULTSPatient Outcomes
The Heparin Citrate Study ACTRN 12609001079235
Table. Patient Outcomes
Citrate (N=105) Heparin/protamine
(N=107)
p
ICU mortality - no./total (%) 28/105 (26.7) 25/107 (23.4) 0.58
ICU Length of Stay - median [IQR], days 9.0 [12] 9.0 [13] 0.79
Hospital mortality - no./total (%) 33/105 (31.4) 31/107 (29.0) 0.7
Red cells transfused
Patients transfused - no./total (%) 52/101 (52) 48/103 (47) 0.58
Volume of red cells - mean (SD) 908 (770) 872 (917) 0.83
RESULTSAdverse Events
The Heparin Citrate Study ACTRN 12609001079235
Table. Adverse Events
ADVERSE EVENT Related to Study Treatment Action
Citrate - 1 Adverse Event
Acidosis, hypotension Definitely Discontinued study treatment
Heparin/protamine - 8 Adverse Events
Bradycardia upon commencing CRRT Definitely Resolved, continued CRRT
HIT - suspected Probably Discontinued study treatment
HIT - suspected Possibly Discontinued study treatment
HIT - confirmed Possibly Discontinued study treatment
Rectal bleeding, normal aPTT Possibly Temporarily discontinued CRRT
Ventricular bigeminy Possibly None, continued CRRT
Ventricular fibrillation Possibly None related to CRRT, continued CRRT
Cardiac arrest (PEA). Chest re-opening. Possibly Temporarily discontinued CRRT
Abbreviations. CRRT = continuous renal replacement therapy, HIT = heparin-induced thrombocytopenia
RESULTSSerious Adverse Events
The Heparin Citrate Study ACTRN 12609001079235
Table. Serious Adverse Events
SERIOUS ADVERSE EVENT Related to Study Treatment Action
Citrate - 1 Serious Adverse Event
Monitoring error, Iatrogenic hypercalcaemia,
reversible myocardial depressionDefinitely Discontinued study treatment
Heparin/protamine - 3 Serious Adverse Events
Unintended crossover to regional citrate, peripheral
infusion of calcium, skin necrosisDefinitely
Plastic surgical review,
staff re-education
HIT - confirmed Definitely Discontinued study treatment
HIT - confirmed Definitely Discontinued study treatment
Abbreviations. HIT = heparin-induced thrombocytopenia
DISCUSSION
Key Points
• Large, multicentre RCT evaluating citrate
• Demonstrates efficacy and technical
improvement of modern citrate CRRT
• Control group was also regional, and
effective
• Clear-cut result, with real consequences..
The Heparin Citrate Study ACTRN 12609001079235
DISCUSSIONHealth Economic Evaluation
The Heparin Citrate Study ACTRN 12609001079235
DISCUSSIONHealth Economic Evaluation
At RPA in 1 year
x1 filter set ~$ 450-500
x1 other consumables ~$ 50-100
~1000 filter sets used in a year
We spend ~ $500 000 per year
The Heparin Citrate Study ACTRN 12609001079235
DISCUSSIONComparison with Previous RCTs
The Heparin Citrate Study ACTRN 12609001079235
Table. Previous RCTs evaluating regional citrate antcoagulation
Author (Year) Centres N (patients) N (filters)
Hetzel 2010 Multi (9) 174 170
Oudemanns-van Straaten 2009 Single 215 200
Fealy 2007 Single 10 20
Betjes 2007 Single 48 142
Kutsogiannis 2005 Multi (3) 30 79
Monchi 2004 Single 20 49
TOTAL PUBLISHED RCTs 497 660
Patients Filters
Heparin citrate study Multi (7) 212 857
CONCLUSION
During CRRT in ICU,
regional citrate anticoagulation,compared to regional heparin/protamine anticoagulation
is associated with
- Half the risk of filter clotting [HR for clotting in hep/prot group 2.03 (95% CI 1.34-3.02, p<0.005)]
- Median filter life 39h v 22.8h (p=0.0037)
- Fewer adverse events
The Heparin Citrate Study ACTRN 12609001079235
Trial Management, Grant Applicants
Rinaldo BellomoCelia BradfordDavid GattasDorrilyn Rajbhandari
Statistician
Serigne Lo – George Institute
Funding
With great THANKS to
The Heparin Citrate (THC) Study
7 TRIAL SITES
Auckland City (NZ)
Shay McGuinness, Rachael Parke, Eileen Gilder
Austin (VIC)
Rinaldo Bellomo, Glenn Eastwood
Dandenong (VIC)
Sanjiv Vij, Katherine Shepherd, Bridget O’Bree
Frankston (VIC)
John Botha, Sharon Allsop, David Lewis
Monash (VIC)
Craig Walker, Pauline Galt, Tammy Lamac
Royal North Shore (NSW)
Celia Bradford, Anne O’Connor
Royal Prince Alfred (NSW)
David Gattas, Dorrilyn Rajbhandari, Heidi Buhr
CRRT:
the details
make a
difference
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