Concomitant use of DOACs with cardiovascular drugs, particularly diuretics, digitalis glycosides, non-dihydropyridine calcium channel blockers, and amiodarone analogs, was associated with significant bleeding interaction signals (adjusted ROR 1.06-2.36).
Observational (n=317,583)
Does concomitant use of cardiovascular drugs increase bleeding events in patients taking DOACs?
Concomitant use of DOACs with specific cardiovascular drugs, particularly digitalis glycosides, NDHP-CCBs, and amiodarone analogs, is associated with increased bleeding risk, highlighting the need for careful risk stratification in polypharmacy.
Estimación del efecto: ROR 1.06-2.36
Background: Patients receiving direct-oral anticoagulants (DOACs) often have multiple cardiovascular disorders and are frequently exposed to polypharmacy.This study aimed to identify bleeding-related drug interactions between DOACs and cardiovascular drugs in the context of polypharmacy using the FDA Adverse Event Reporting System (FAERS).Methods: Individual case safety reports involving apixaban, dabigatran, edoxaban, or rivaroxaban were extracted from FAERS.DOAC-related reports were classified according to exposure to concomitant use of predefined 15 drug classes of interest-ten cardiovascular drug classes, three classes of pharmacokinetic modifiers, anti-platelets, and non-steroidal anti-inflammatory drugsand bleeding events.Bleeding events were defined at three levels: haemorrhage-related events, actual bleeding events, and major bleeding.Major bleeding was further classified by anatomical site.Exact matching and logistic regression were performed to estimate adjusted reporting odds ratios.Results: A total of 317,583 eligible reports were included.Fifteen DOAC-drug combinations were consistently identified as significant interaction signals across the three bleeding definitions, with adjusted RORs ranging from 1.06 to 2.36.Diuretics showed consistent interaction signals across DOACs and bleeding definitions, while the strongest interaction signals were observed with digitalis glycosides, non-dihydropyridine calcium channel blockers, and amiodarone analogs.Site-stratified major bleeding analyses identified 64 significant interaction signals, with rivaroxaban accounting for the largest proportion, whereas edoxaban showed a relatively less extensive interaction signal profile. Conclusions: These findings suggest that consideration of polypharmacy and potential drug interactions may improve DOAC selection and risk stratification, particularly with concomitant cardiovascular drugs and site-specific bleeding risk, supporting closer monitoring Clinical significance Potential drug interactions should be assessed in polypharmacy, particularly direct-oral anticoagulants plus diuretics, digitalis glycosides, non-dihydropyridine calcium channel blockers, or amiodarone analogs, as these combinations show hemorrhagic interaction signals warranting closer monitoring and risk optimization. Rivaroxaban showed a broader bleeding-related interaction signal profile, whereas edoxaban showed fewer signals. Site-specific analyses revealed interaction-associated bleeding risk increase mainly at intracranial, gastrointestinal, and pericardial sites, which carry substantial clinical importance.7,721 36,496 12,551 46,300 0.78 (0.76-0.81) 0.86 (0.83-0.90)Actual bleeding events c 6,783 37,434 10,978 47,873 0.79 (0.76-0.82) 0.88 (0.85-0.91)Major bleeding d 3,932 40,285 5,525 53,326 0.94 (0.90-0.98) 1.00 (0.95-1.05)Angiotensin converting enzyme inhibitors Haemorrhage-related events 2,858 13,058 17,369 69,521 0.88 (0.84-0.92) 0.98 (0.94-1.03)Actual bleeding events 2,506 13,410 15,233 71,657 0.88 (0.84-0.92) 0.99 (0.94-1.04)Major bleeding 1,464 14,452 7,982 78,908 1.00 (0.94-1.06) 1.06 (0.99-1.13)Angiotensin receptor blockers Haemorrhage-related events 3,507 15,218 16,747 67,444 0.93 (0.89-0.97) 1.03 (0.98-1.08)Actual bleeding events 3,076 15,649 14,671 69,520 0.93 (0.89-0.97) 1.03 (0.98-1.08)Major bleeding 1,726 16,999 7,724 76,467 1.01 (0.95-1.06) 1.04 (0.98-1.11)Dihydropyridinecalcium channel blocekrs Haemorrhage-related events 2,888 12,625 17,354 70,000 0.92 (0.88-0.96) 1.08 (1.03-1.13)Actual bleeding events 2,560 12,953 15,187 72,167 0.94 (0.90-0.98) 1.12 (1.06-1.17)Major bleeding 1,530 13,983 7,922 79,432 1.10 (1.04-1.16)1.24 (1.17-1.32)Nondihydropyridinecalcium channel blocekrs Haemorrhage-related events 1,159 5,447 19,049 77,066 0.86 (0.81-0.92) 0.85 (0.79-0.92)Actual bleeding events 996 5,610 16,723 79,392 0.84 (0.79-0.90) 0.86 (0.79-0.93)Major bleeding 463 6,143 8,970 87,145 0.73 (0.66-0.81) 0.76 (0.68-0.85)Amiodarone analogs Haemorrhage-related events 1,507 7,090 18,583 74,808 0.86 (0.81-0.91) 0.78 (0.71-0.85)Actual bleeding events 1,292 7,305 16,333 77,058 0.83 (0.78-0.89) 0.78 (0.70-0.86)Major bleeding 669 7,928 8,749 84,642 0.82 (0.75-0.89) 0.74 (0.65-0.84)Digitalis glycosides Haemorrhage-related events 1,228 3,757 18,696 77,373 1.35 (1.27-1.45)1.65 (1.50-1.80)Actual bleeding events 1,153 3,832 16,320 79,749 1.47 (1.37-1.57)1.84 (1.68-2.02)Major bleeding 796 4,189 8,551 87,518 1.94 (1.80-2.10)2.36 (2.10-2.65)Diuretics Haemorrhage-related events b 6,614 28,792 13,652 53,925 0.91 (0.88-0.94) 1.16 (1.11-1.20)Actual bleeding events c 5,874 29,532 11,881 55,696 0.93 (0.90-0.96) 1.21 (1.16-1.26)Major bleeding 3,303 32,103 6,152 61,425 1.03 (0.98-1.07) 1.22 (1.16-1.29)HMG-CoA reductase inhibitors Haemorrhage-related events b 6,260 28,734 14,014 54,027 0.84 (0.81-0.87) 0.93 (0.90-0.97)
Cheon et al. (Fri,) conducted a observational in Patients receiving direct-oral anticoagulants (DOACs) (n=317,583). DOACs with concomitant cardiovascular drugs vs. DOAC alone was evaluated on Bleeding events (haemorrhage-related events, actual bleeding events, and major bleeding) (ROR 1.06-2.36). Concomitant use of DOACs with cardiovascular drugs, particularly diuretics, digitalis glycosides, non-dihydropyridine calcium channel blockers, and amiodarone analogs, was associated with significant bleeding interaction signals (adjusted ROR 1.06-2.36).