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![RESULTS
Number 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](https://image.slidesharecdn.com/gattascitrateanzicsnsw20140910-141208223834-conversion-gate01/75/The-Citrate-Story-by-David-Gattas-18-2048.jpg)
![RESULTS
Patient Outcomes
Table. Patient Outcomes
The Heparin Citrate Study ACTRN 12609001079235
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](https://image.slidesharecdn.com/gattascitrateanzicsnsw20140910-141208223834-conversion-gate01/75/The-Citrate-Story-by-David-Gattas-27-2048.jpg)
![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](https://image.slidesharecdn.com/gattascitrateanzicsnsw20140910-141208223834-conversion-gate01/75/The-Citrate-Story-by-David-Gattas-35-2048.jpg)
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The Citrate Story by David Gattas
The Heparin Citrate (THC) study evaluates the effectiveness of regional citrate anticoagulation compared to regional heparin/protamine anticoagulation in maintaining functional filter life during continuous renal replacement therapy (CRRT) in ICU patients. Results indicate that citrate anticoagulation is associated with a 50% lower risk of filter clotting and longer median filter life (39 hours versus 22.8 hours). Adverse events were fewer in the citrate group, highlighting its safety and efficacy for CRRT.
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The Citrate Story by David Gattas
- 1. CITRATE in CRRT David Gattas [email protected] @dgattas
- 2. CRRT: What areyou trying to ACHIEVE? Solute control? Fluid removal? Improve a life? Save a life?
- 5. This is aTECHNICAL task Requiring technical SKILLS
- 6. PATIENTS ONLY LIKE INTENSIVISTS WHO HAVE GREAT CRRT FILTER LIFE SKILLS
- 7. The Heparin Citrate(THC) Study A randomised controlled study comparing the effect of two different anticoagulation regimens on filter life during Continuous Renal Replacement Therapy (CRRT) ACTRN 12609001079235 David Gattas MBBS MMed (ClinEpi), FRACP FCICM Senior Staff Specialist, Intensive Care, Royal Prince Alfred Hospital Clinical Associate Professor, Sydney Medical School, University of Sydney [email protected]
- 8. The Heparin Citrate(THC) Study With great THANKS to Trial Management, Grant Applicants Rinaldo Bellomo Celia Bradford David Gattas Dorrilyn Rajbhandari Statistician Serigne Lo – George Institute Funding Funded 2010, AUD $55 000 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 SLHD (RPAH Zone) HREC Approval: X09-0068 & HREC/09/RPAH/98
- 9. AIM To testthe hypothesis that regional citrate anticoagulation is more effective than regional heparin/protamine anticoagulation at maintaining functional filter life in patients receiving CRRT The Heparin Citrate Study ACTRN 12609001079235
- 10. INCLUSION Commencing CRRTfor 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 EXCLUSION Age <18y Expected <24h in ICU Contraindication to intervention or control (eg liver, H.I.T) Expected difficulty adhering to allocated group The Heparin Citrate Study ACTRN 12609001079235
- 11. DESIGN Randomised controlledtrial SETTING Seven ICUs in Australia and NZ 2 in NSW, 4 in VIC, 1 NZ Tertiary, metropolitan SAMPLE SIZE: 220 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 The Heparin Citrate Study ACTRN 12609001079235
- 12. CRRT CIRCUIT ANTICOAGULATION INTERVENTION Regional citrate anticoagulation CONTROL Regional heparin/protamine 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) The Heparin Citrate Study ACTRN 12609001079235
- 13. PRIMARY OUTCOME Functionalfilter 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
- 14. 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
- 15. STATISTICS – FILTERLIFE for 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
- 16. RESULTS Flow Diagram Recruiting: Jan 2010 - Jan 2013 The Heparin Citrate Study ACTRN 12609001079235
- 17. RESULTS Flow Diagram The Heparin Citrate Study ACTRN 12609001079235 100% of patients followed up for hospital mortality
- 18. RESULTS Number ofFilters 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
- 19. RESULTS Baseline Characteristics– basic demographics Table. Baseline characteristics of the intervention and control group The Heparin Citrate Study ACTRN 12609001079235 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
- 20. RESULTS Baseline Characteristics– diagnosis and severity Table. Baseline characteristics of the intervention and control group 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) 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 (%) 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) The Heparin Citrate Study ACTRN 12609001079235 Citrate (N=105) Heparin/protamine (N=107) Other 62/105 (59.0) 67/107 (62.6) Renal 45/101 (44.5) 51/106 (48.1) Liver 3/101 (3.0) 7/106 (6.6) ~ 12% cardiac surgery, ~8 %septic shock, well matched groups including severity of illness
- 21. RESULTS Baseline Characteristics– vent, inotrope, labs Table. Baseline characteristics of the intervention and control group 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) The Heparin Citrate Study ACTRN 12609001079235 Citrate (N=105) Heparin/protamine (N=107) INR 1.5 (1.2) 1.4 (0.52) APTT (s) 40 (18) 40 (14) ~73% patients ventilated, ~67% inotropes Well matched at baseline for renal and haematological parameters
- 23. RESULTS Primary Outcome 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 Analysis of Maximum Likelihood Estimates Parameter DF Parameter Estimate 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 The Heparin Citrate Study ACTRN 12609001079235 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 Cox model with random effect by subject
- 24. RESULTS Primary Outcome Citrate median 39h (100 filters*) vs Hep/prot median 22.8h (104 filters*) Log rank p= 0.0037 The Heparin Citrate Study ACTRN 12609001079235 • Includes the first filter in each patient ONLY
- 25. RESULTS Number ofFilters, Duration of CRRT Number of filters included in the study* Citrate Heparin/ protamine 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 Regional citrate anticoagulation was associated with use of fewer filters, less clotted filters and longer cumulative duration of CRRT Total The Heparin Citrate Study ACTRN 12609001079235 * filter outcome adjudicated by 2 independent intensivists
- 26. RESULTS Clotted FiltersOnly 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
- 27. RESULTS Patient Outcomes Table. Patient Outcomes The Heparin Citrate Study ACTRN 12609001079235 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
- 28. RESULTS Adverse 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 The Heparin Citrate Study ACTRN 12609001079235
- 29. RESULTS Serious AdverseEvents Table. Serious Adverse Events SERIOUS ADVERSE EVENT Related to Study Treatment Action Citrate - 1 Serious Adverse Event Monitoring error, Iatrogenic hypercalcaemia, reversible myocardial depression The Heparin Citrate Study ACTRN 12609001079235 Definitely Discontinued study treatment Heparin/protamine - 3 Serious Adverse Events Unintended crossover to regional citrate, peripheral infusion of calcium, skin necrosis Definitely Plastic surgical review, staff re-education HIT - confirmed Definitely Discontinued study treatment HIT - confirmed Definitely Discontinued study treatment Abbreviations. HIT = heparin-induced thrombocytopenia
- 30. 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
- 31. DISCUSSION Health EconomicEvaluation The Heparin Citrate Study ACTRN 12609001079235
- 32. DISCUSSION Health EconomicEvaluation 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
- 33. DISCUSSION Comparison withPrevious 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 The Heparin Citrate Study ACTRN 12609001079235 Patients Filters Heparin citrate study Multi (7) 212 857
- 35. CONCLUSION During CRRTin 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
- 36. The Heparin Citrate(THC) Study With great THANKS to Trial Management, Grant Applicants Rinaldo Bellomo Celia Bradford David Gattas Dorrilyn Rajbhandari Statistician Serigne Lo – George Institute Funding 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
- 37. CRRT: the details make a difference
Editor's Notes
- #5 This is a technical skill with technical goals: FILTER LIFE
- #6 This is a technical skill with technical goals: FILTER LIFE
- #7 Napoleon Dynamite: I don't even have any skills. Pedro: What do you mean? Napoleon Dynamite: You know, like nunchuck skills, bow hunting skills, computer hacking skills. Girls only like guys who have great skills.
- #14 413 of 857 (48%) were referred for adjudication
- #16 Heterogeneity can be thought of as filter life being in an individual patient cluster My data showed no dependence Filters that are electively stopped (incl at 72h) are included but censored in survival analysis Excluding non-clotted filters will exclude all filters running smoothly at the time of an elective stoppage, including those changed at 72h as per manufacturer’s spec. The maximum life expectancy is therefore 72h and this is a successful filter. Correlated event times are common in the study of health and related sciences. Correlation may occur when individuals experiencing a single event belong to groups or clusters, such as families or treatment centres, respectively. Alternatively, correlation may be due to recurrent events processes—where the subject experiences the same type of event more than once, such as hospital stays or heart attacks. In the case of recurrent events, correlation can come from two distinct sources: 1. Heterogeneity across individuals: In any study, some cases have a higher or lower event rate than other cases due to unknown, unmeasured, or unmeasurable eects. Individuals have varied lifestyles, genetic traits, and experiences, for example, which inuence the likelihood that they will succumb to disease but either cannot be measured or are unknown. As a result, some individuals are more prone to disease, experiencing their rst, second, third, etc., disease recurrence more quickly than other individuals. This introduces heterogeneity across individuals and produces within-subject correlation in the occurrence and timing of recurrent events within a given subject. At the same time, response rates can be homogeneous within individuals producing within-subject correlation in event times. 2. Event dependence: The occurrence of one event may make further events more or less likely. This event (or occurrence) dependence may be produced by a biological weakening (damage eects) or strengthening (resistance eects). Either of these phenomenon implies that the risk for an event is a function of the occurrence of previous spells. This creates within subject correlation as well. Medical research and clinical experience suggest that both heterogeneity and event dependence are likely to be the rule, rather than the exception, in the study of recurrent events. *The citrate data showed no evidence of dependence* hence Cox model with adjustment for a filter’s subject ID was the most appropriate model
- #25 Kaplan-Meier analysis required events to be completely independent. Hence, this plot includes only the first clotted filter for each patient
- #26 Clotted 226 of 390 = 58% of citrate filters clotted 310 of 467 = 66% of hep/prot filters clotted Didn’t clot 127 of 390 = 33% citrate filters didn’t clot 112 of 467 = 24% of hep/prot filters didn’t clot
- #37 IntroductionBecause of ongoing controversy, renal and vital outcomes are compared between systemically administered unfractionated heparin and regional anticoagulation with citrate-buffered replacement solution in predilution mode, during continuous venovenous hemofiltration (CVVH) in critically ill patients with acute kidney injury (AKI).MethodsIn this multi-center randomized controlled trial, patients admitted to the intensive care unit requiring CVVH and meeting inclusion criteria, were randomly assigned to citrate or heparin. Primary endpoints were mortality and renal outcome in intention-to-treat analysis. Secondary endpoints were safety and efficacy. Safety was defined as absence of any adverse event necessitating discontinuation of the assigned anticoagulant. For efficacy, among other parameters, survival times of the first hemofilter were studied.ResultsOf the 139 patients enrolled, 66 were randomized to citrate and 73 to heparin. Mortality rates at 28 and 90?days did not differ between groups: 22/66 (33%) of citrate-treated patients died versus 25/72 (35%) of heparin-treated patients at 28?days, and 27/65 (42%) of citrate-treated patients died versus 29/69 (42%) of heparin-treated patients at 90?days (P?=?1.00 for both). Renal outcome, i.e. independency of renal replacement therapy 28?days after initiation of CVVH in surviving patients, did not differ between groups: 29/43 (67%) in the citrate-treated patients versus 33/47 (70%) in heparin-treated patients (P?=?0.82). Heparin was discontinued in 24/73 (33%) of patients whereas citrate was discontinued in 5/66 (8%) of patients (P?<?0.001). Filter survival times were superior for citrate (median 46 versus 32?hours, P?=?0.02), as were the number of filters used (P?=?0.002) and the off time within 72?hours (P?=?0.002). The costs during the first 72?hours of prescribed CVVH were lower in citrate-based CVVH.ConclusionsRenal outcome and patient mortality were similar for citrate and heparin anticoagulation during CVVH in the critically ill patient with AKI. However, citrate was superior in terms of safety, efficacy and costs.Trial registrationClinicaltrials.gov NCT00209378. Registered 13th September 2005.