Exclusion criteria for liver disease of select randomized clinical trials of the direct oral anticoagulants for VTE
| Trial . | Population . | Exclusion criteria . |
|---|---|---|
| AMPLIFY (2013) | Acute VTE | ALT or AST >2 x ULN, bilirubin >1.5 x ULN (unless an alternative factor is identified [eg, Gilbert's syndrome]), active and clinically significant liver disease (eg, hepatorenal syndrome) |
| AMPLIFY-EXT (2013) | Extended VTE | ALT or AST >2 × ULN, bilirubin >1.5 × ULN (unless an alternative factor is identified [eg, Gilbert's syndrome]), active and clinically significant liver disease (eg, hepatorenal syndrome) |
| EINSTEIN CHOICE (2017) | Extended VTE | Hepatic disease associated with coagulopathy leading to a clinically relevant bleeding risk |
| EINSTEIN DVT (2010) | Acute DVT | Significant liver disease (eg, acute hepatitis, chronic active hepatitis, cirrhosis) or ALT >3 × ULN |
| EINSTEIN-EXT (2010) | Extended VTE | Significant liver disease (eg, acute hepatitis, chronic active hepatitis, cirrhosis) or ALT >3 × ULN |
| EINSTEIN PE (2012) | Acute PE | Significant liver disease (eg, acute hepatitis, chronic active hepatitis, cirrhosis) or ALT >3 × ULN |
| Hokusai VTE (2013) | Acute VTE | Significant liver disease (e.g., acute hepatitis, chronic active hepatitis, cirrhosis) or ALT ≥2 × ULN, or total bilirubin 1.5 × ULN |
| RE-COVER (2009) | Acute VTE | Liver disease with aminotransferase level that was >2 × ULN, known liver disease expected to have an impact on survival |
| RE-COVER II (2014) | Acute VTE | Liver disease with aminotransferase level that was >3 × the ULN, known liver disease expected to have an impact on survival |
| RE-MEDY (2013) | Extended VTE | AST or ALT >2 × ULN, liver disease expected to have any potential impact on survival (eg, acute hepatitis or possibly active hepatitis B, hepatitis C or cirrhosis, but not Gilbert's syndrome or hepatitis A with complete recovery) |
| RE-SONATE (2013) | Extended VTE | Active liver disease or liver disease decreasing survival (eg, acute hepatitis, chronic active hepatitis, cirrhosis) or ALT >3 × ULN |
| Trial . | Population . | Exclusion criteria . |
|---|---|---|
| AMPLIFY (2013) | Acute VTE | ALT or AST >2 x ULN, bilirubin >1.5 x ULN (unless an alternative factor is identified [eg, Gilbert's syndrome]), active and clinically significant liver disease (eg, hepatorenal syndrome) |
| AMPLIFY-EXT (2013) | Extended VTE | ALT or AST >2 × ULN, bilirubin >1.5 × ULN (unless an alternative factor is identified [eg, Gilbert's syndrome]), active and clinically significant liver disease (eg, hepatorenal syndrome) |
| EINSTEIN CHOICE (2017) | Extended VTE | Hepatic disease associated with coagulopathy leading to a clinically relevant bleeding risk |
| EINSTEIN DVT (2010) | Acute DVT | Significant liver disease (eg, acute hepatitis, chronic active hepatitis, cirrhosis) or ALT >3 × ULN |
| EINSTEIN-EXT (2010) | Extended VTE | Significant liver disease (eg, acute hepatitis, chronic active hepatitis, cirrhosis) or ALT >3 × ULN |
| EINSTEIN PE (2012) | Acute PE | Significant liver disease (eg, acute hepatitis, chronic active hepatitis, cirrhosis) or ALT >3 × ULN |
| Hokusai VTE (2013) | Acute VTE | Significant liver disease (e.g., acute hepatitis, chronic active hepatitis, cirrhosis) or ALT ≥2 × ULN, or total bilirubin 1.5 × ULN |
| RE-COVER (2009) | Acute VTE | Liver disease with aminotransferase level that was >2 × ULN, known liver disease expected to have an impact on survival |
| RE-COVER II (2014) | Acute VTE | Liver disease with aminotransferase level that was >3 × the ULN, known liver disease expected to have an impact on survival |
| RE-MEDY (2013) | Extended VTE | AST or ALT >2 × ULN, liver disease expected to have any potential impact on survival (eg, acute hepatitis or possibly active hepatitis B, hepatitis C or cirrhosis, but not Gilbert's syndrome or hepatitis A with complete recovery) |
| RE-SONATE (2013) | Extended VTE | Active liver disease or liver disease decreasing survival (eg, acute hepatitis, chronic active hepatitis, cirrhosis) or ALT >3 × ULN |
| Drug . | CYP metabolism . | Degree of renal clearancea . |
|---|---|---|
| Apixaban | Mostly CYP3A4 | ~27% |
| Dabigatran | No | ~80% |
| Edoxaban | Minimal | ~50% |
| Rivaroxaban | CYP 3A4/5, CYP2J2 | ~66% |
| Drug . | CYP metabolism . | Degree of renal clearancea . |
|---|---|---|
| Apixaban | Mostly CYP3A4 | ~27% |
| Dabigatran | No | ~80% |
| Edoxaban | Minimal | ~50% |
| Rivaroxaban | CYP 3A4/5, CYP2J2 | ~66% |
The exact hepatic portion of DOAC clearance cannot be directly estimated given variable elimination via biliary excretion and direct intestinal excretion.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CYP, cytochrome P; DVT, deep vein thrombosis; ULN, upper limit of normal; VTE, venous thromboembolism.