Heparin versus citrate anticoagulation for continuous renal replacement therapy in intensive care: the RRAM observational study
Authors: Gould Doug W , Doidge James , Sadique M Zia , Borthwick Mark , Hatch Robert , Caskey Fergus J , Forni Lui , Lawrence Robert F , MacEwen Clare , Ostermann Marlies , Mouncey Paul R , Harrison David A , Rowan Kathryn M , Young J Duncan , Watkinson Peter J 
Published: February 2022

Background
In the UK, 10% of admissions to intensive care units receive continuous renal replacement therapy with regional citrate anticoagulation replacing systemic heparin anticoagulation over the last decade. Regional citrate anticoagulation is now used in > 50% of intensive care units, despite little evidence of safety or effectiveness.

Aim
The aim of the Renal Replacement Anticoagulant Management study was to evaluate the clinical and health economic impacts of intensive care units moving from systemic heparin anticoagulation to regional citrate anticoagulation for continuous renal replacement therapy.

Design
This was an observational comparative effectiveness study.

Setting
The setting was NHS adult general intensive care units in England and Wales.

Participants
Participants were adults receiving continuous renal replacement therapy in an intensive care unit participating in the Intensive Care National Audit & Research Centre Case Mix Programme national clinical audit between 1 April 2009 and 31 March 2017.

Interventions
Exposure – continuous renal replacement therapy in an intensive care unit after completion of transition to regional citrate anticoagulation. Comparator – continuous renal replacement therapy in an intensive care unit before starting transition to regional citrate anticoagulation or had not transitioned.

Outcome measures
Primary effectiveness – all-cause mortality at 90 days. Primary economic – incremental net monetary benefit at 1 year. Secondary outcomes – mortality at hospital discharge, 30 days and 1 year; days of renal, cardiovascular and advanced respiratory support in intensive care unit; length of stay in intensive care unit and hospital; bleeding and thromboembolic events; prevalence of end-stage renal disease at 1 year; and estimated lifetime incremental net monetary benefit.

Data sources
Individual patient data from the Intensive Care National Audit & Research Centre Case Mix Programme were linked with the UK Renal Registry, Hospital Episode Statistics (for England), Patient Episodes Data for Wales and Civil Registrations (Deaths) data sets, and combined with identified periods of systemic heparin anticoagulation and regional citrate anticoagulation (survey of intensive care units). Staff time and consumables were obtained from micro-costing. Continuous renal replacement therapy system failures were estimated from the Post-Intensive Care Risk-adjusted Alerting and Monitoring data set. EuroQol-3 Dimensions, three-level version, health-related quality of life was obtained from the Intensive Care Outcomes Network study.

Results
Out of the 188 (94.9%) units that responded to the survey, 182 (96.8%) use continuous renal replacement therapy. After linkage, data were available from 69,001 patients across 181 intensive care units (60,416 during periods of systemic heparin anticoagulation use and 8585 during regional citrate anticoagulation use). The change to regional citrate anticoagulation was not associated with a step change in 90-day mortality (odds ratio 0.98, 95% confidence interval 0.89 to 1.08). Secondary outcomes showed step increases in days of renal support (difference in means 0.53 days, 95% confidence interval 0.28 to 0.79 days), advanced cardiovascular support (difference in means 0.23 days, 95% confidence interval 0.09 to 0.38 days) and advanced respiratory support (difference in means, 0.53 days, 95% CI 0.03 to 1.03 days) with a trend toward fewer bleeding episodes (odds ratio 0.90, 95% confidence interval 0.76 to 1.06) with transition to regional citrate anticoagulation. The micro-costing study indicated that regional citrate anticoagulation was more expensive and was associated with an estimated incremental net monetary loss (step change) of –£2376 (95% confidence interval –£3841 to –£911). The estimated likelihood of cost-effectiveness at 1 year was less than 0.1%.

Limitations
Lack of patient-level treatment data means that the results represent average effects of changing to regional citrate anticoagulation in intensive care units. Administrative data are subject to variation in data quality over time, which may contribute to observed trends.

Conclusions
The introduction of regional citrate anticoagulation has not improved outcomes for patients and is likely to have substantially increased costs. This study demonstrates the feasibility of evaluating effects of changes in practice using routinely collected data.

Future work
(1) Prioritise other changes in clinical practice for evaluation and (2) methodological research to understand potential implications of trends in data quality.

Trial registration
This trial is registered as ClinicalTrials.gov NCT03545750.

Funding
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 13. See the NIHR Journals Library website for further project information.