The Citrate Story by David Gattas

CITRATE

in

CRRTDavid Gattas

[email protected]

@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

[email protected]

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


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


DESIGN

Randomised controlled trial

SETTING

SAMPLE SIZE: 220

Seven ICUs in Australia and NZ

2 in NSW, 4 in VIC, 1 NZ

Tertiary, metropolitan


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


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


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


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


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


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


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




~ 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




~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


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


Citrate median 16.5h (226 filters)

vs

Hep/prot median 11.8h (310 filters)

(Mann-Whitney U) p<0.0001

RESULTSPatient Outcomes


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


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


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..


DISCUSSIONHealth Economic Evaluation


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


DISCUSSIONComparison with Previous RCTs


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


Trial Management, Grant Applicants

Rinaldo BellomoCelia BradfordDavid GattasDorrilyn Rajbhandari

Statistician

Serigne Lo – George Institute

Funding

With great THANKS to


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

Health & Medicine

The Citrate Story by David Gattas