Effect of Regional Citrate Anticoagulation vs Systemic Heparin Anticoagulation During Continuous Kidney Replacement Therapy on Dialysis Filter Life Span and Mortality Among Critically Ill Patients With Acute Kidney InjuryA Randomized Clinical Trial

The blog is written by Dr Jose Chacko

Design

The study was performed against the background of the KDIGO (2012) guidelines that recommended the use of regional citrate anticoagulation instead of heparin during renal replacement therapy in acute kidney injury in patients who have no impairment of coagulation, no increase in bleeding risk, and not receiving systemic anticoagulation for comorbid conditions.

The RICH trial was a randomized, multicenter, parallel-group clinical trial that compared  regional citrate anticoagulation with unfractionated heparin in patients who underwent CRRT in AKI. A computerized randomization method provided balanced treatment assignment based on study center, gender, the cardiovascular SOFA score (0-2 vs 3-4), and presence of oliguria

Setting

The study was carried out between March 2016 to December 2018 in 26 intensive care units in Germany.

Population

Inclusion: (1) KDIGO stage 3 AKI (urine output <0.3 mL/kg/h for ≥24 hours, and/or >3-fold increase in serum creatinine level compared with baseline, and/or serum creatinine level of ≥4 mg/dL [353.6 μmol/L] with an acute increase of at least 0.5 mg/dL [44.2 μmol/L] within 48 hours) OR an absolute indication for continuous renal replacement therapy (serum urea levels >150 mg/dL, serum potassium levels >6 mmol/L, serum magnesium levels >9.7 mg/dL [4 mmol/L], blood pH <7.15, urine production <200 mL/12 h or anuria, or fluid overload with edema in the presence of acute kidney injury resistant to diuretic treatment); (2) at least one additional condition (severe sepsis or septic shock, use of vasopressor, refractory fluid overload); (3) age between 18 and 90 years; (4) expected to offer full ICU support for a minimum of 3 days

Exclusion: Increased bleeding risk, had diseases with hemorrhagic diathesis, needed therapeutic anticoagulation, had previous allergic reactions to one of the anticoagulants, had known heparin-induced thrombocytopenia, or had persistent and severe lactic acidosis (pH <7.2 in 2 consecutive measurements for >2 hours and lactate level >72.1 mg/dL [8 mmol/L]) in the context of acute liver failure, shock, or both

Intervention

Regional citrate anticoagulation was infused pre-filter and titrated to ionized calcium level 0.25- 0.35 mmol/L, measured post-filter. A standardized protocol was followed.

Control

Systemic anticoagulation with heparin targeting an activated partial thromboplastin of 45–60 seconds.

Common management

CRRT was commenced within 24 hours of reaching KDIGO stage 3 criteria. In patients who fulfilled criteria for absolute indication, therapy was commenced as early as possible.

A dose of 30 mL/kg/h was prescribed, to achieve at least 20–25 ml/kg/h. Blood flow: 100 ml/min; filters were changed every 72 hours. Depending on the patient’s condition, CRRT could be switched to an intermittent technique starting from 5 days after randomization.

Statistics

The mean difference in filter life span between the regional citrate and heparin was expected to be at least 5 hours. The 90-d mortality was assumed to be 48%. The 90-day mortality rate in the regional citrate anticoagulation expected to be 40% or lower (absolute reduction by 8%, based on the RENAL study). The sample size was calculated for 90% power for filter life and 80% power for 90-d mortality. Interim and final statistical analysis was planned after enrollment of 400 and 1260 patients. A nonbinding stopping rule for futility was specified for the second coprimary outcome of 90-day mortality.

Recruitment was ceased midway for significant effectiveness in terms of the first coprimary outcome of filter life span and for futility in terms of the second coprimary outcome of 90-day mortality

Primary outcome (co-primary outcomes)

1. Dialysis filter life span – 44.9 % vs 33.2% ( p<0.001)

90-day all-cause mortality – 51.2 vs 53.6 ( p>0.05)

Secondary outcomes

Bleeding – 5.1 vs 16.9 % ( p<0.001)

Infection – 68% vs 55.3% ( p< 0.001)

Adverse events

Citrate group: more metabolic alkalosis, hypophosphatemia, higher incidence of infections. Less gastrointestinal complications

Heparin group: more hyperkalemia

Surgical vs. non-surgical patients

No difference in primary/secondary outcomes with surgical vs. non-surgical patients

Post-hoc analysis

Multivariable analysis (anticoagulation strategy, study centre, cardiovascular SOFA score, presence or absence of oliguria, gender) filter life was longest with CVVHD, followed by CVVHDF, and shortest with CVVH.

Author’s conclusions

Among critically ill patients with acute kidney injury receiving continuous kidney replacement therapy, anticoagulation with regional citrate, compared with systemic heparin anti-coagulation, resulted in significantly longer filter life span. The trial was terminated early and was therefore underpowered to reach conclusions about the effect of anticoagulation strategy on mortality.

Limitations

• 4431/5069 (87.4%) patients were excluded
• Unblinded
• The study was underpowered for 90-d mortality as an endpoint as it was stopped early for futility 
• Forty-two patients had to be excluded from the analysis because of the incomplete consent process
• Nineteen patients were lost to follow-up for the endpoint 90-day mortality
• Patients with increased bleeding risk were excluded; these are the patients who might benefit from regional anticoagulation

Summary – 

Citrate anticoagulation strategy can be considered as a default anticoagulation strategy for CRRT,  as it significantly prolongs the filter life span.