What is the clinical evidence from this study?

Study design: Observational. Population: Patients receiving direct-oral anticoagulants (DOACs) (n=317583). Intervention: DOACs with concomitant cardiovascular drugs vs. DOAC alone. Primary outcome: Bleeding events (haemorrhage-related events, actual bleeding events, and major bleeding) (ROR 1.06-2.36).

What question did this study set out to answer?

This study aims to identify bleeding-related interactions between direct oral anticoagulants (DOACs) and cardiovascular drugs in patients undergoing polypharmacy.

May 8, 2026Open Access

Bleeding-Related Interactions Between DOACs and Cardiovascular Drugs: Insights from FDA adverse event reporting system

Key Result

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).

Key Points

This study aims to identify bleeding-related interactions between direct oral anticoagulants (DOACs) and cardiovascular drugs in patients undergoing polypharmacy.
Extracted individual case safety reports from the FDA Adverse Event Reporting System (FAERS) for specific DOACs
Classified reports based on exposure to 15 drug classes and bleeding events
Utilized exact matching and logistic regression to estimate adjusted reporting odds ratios (RORs).
317,583 reports were included, identifying 15 significant DOAC-drug combinations across bleeding definitions with RORs from 1.06 to 2.36.
Digitalis glycosides, non-dihydropyridine calcium channel blockers, and amiodarone analogs had the strongest interaction signals with DOACs.
Site analyses showed major bleeding risk increased at intracranial, gastrointestinal, and pericardial locations.

Study Design

Type

Observational (n=317,583)

Structured PICO

Does concomitant use of cardiovascular drugs increase bleeding events in patients taking DOACs?

Population

317,583 individual case safety reports from the FDA Adverse Event Reporting System (FAERS) involving apixaban, dabigatran, edoxaban, or rivaroxaban, excluding reports with multiple DOACs, warfarin use, or missing age/sex.

Intervention

Concomitant use of DOACs with 15 predefined drug classes (10 cardiovascular drug classes, 3 pharmacokinetic modifiers, anti-platelets, and NSAIDs)

Comparator

DOAC use without exposure to the specific concomitant drugs of interest

Outcome

Bleeding events defined at three levels: haemorrhage-related events, actual bleeding events, and major bleeding (classified by anatomical site)safety

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.

Main Result

Effect estimate: ROR 1.06-2.36

Limitations

FAERS data are inherently constrained by biases such as underreporting, selective or stimulated reporting, and lack of denominator data
Information on concomitant medications is often incomplete
Major bleeding was defined based on anatomical sites, as severity and laboratory findings are limited in FAERS
A causal relationship between specific drug combinations and bleeding events cannot be confirmed

Abstract

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)

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