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Summary

  1. Top of page
  2. Summary
  3. Review Criteria
  4. Introduction
  5. New and emerging oral anticoagulants
  6. Food interactions
  7. Metabolism
  8. Drug interactions
  9. The potential impact in the US patient population
  10. Conclusion
  11. Author contributions
  12. Acknowledgements
  13. References

Oral warfarin is associated with extensive food and drug interactions, and there is a need to consider such interactions with the new oral anticoagulants (OACs) dabigatran etexilate, rivaroxaban and apixaban. A literature survey was conducted using PubMed, EMBASE and recent abstracts from thrombosis meetings to identify publications related to food, drug and dietary supplement interaction studies with dabigatran etexilate, rivaroxaban and apixaban. Clinical experience regarding food interactions is currently limited. Regarding drug–drug interactions, dabigatran requires caution when used in combination with strong inhibitors or inducers of P-glycoprotein, such as amiodarone or rifampicin. Rivaroxaban (and possibly apixaban) is contraindicated in combination with drugs that strongly inhibit both cytochrome P450 3A4 and P-glycoprotein, such as azole antimycotics, and caution is required when used in combination with strong inhibitors of only one of these pathways. Important drug interactions of the new OACs that can lead to adverse clinical reactions may also occur with non-steroidal anti-inflammatory drugs and antiplatelet drugs, such as aspirin and clopidogrel. Over-the-counter (OTC) medications and food supplements (e.g. St. John’s Wort) may also interact with the new OACs. Given the common long-term use of drugs for some chronic disorders, the frequent use of OTC medications and the need for multiple treatments in special populations, such as the elderly people, it is essential that the issue of drug interactions is properly evaluated. New OACs offer significant potential advantages to the field of venous thromboprophylaxis, but we should not fail to appreciate their lack of extensive clinical experience.


Review Criteria

  1. Top of page
  2. Summary
  3. Review Criteria
  4. Introduction
  5. New and emerging oral anticoagulants
  6. Food interactions
  7. Metabolism
  8. Drug interactions
  9. The potential impact in the US patient population
  10. Conclusion
  11. Author contributions
  12. Acknowledgements
  13. References

We conducted a literature search using PubMed, EMBASE and recent abstracts from thrombosis meetings to identify publications related to food, drug and dietary supplement interaction studies with the new oral anticoagulants, dabigatran etexilate, rivaroxaban and apixaban. In the absence of peer-reviewed publications, some information was extracted from the product monographs, which do not contain detailed information about clinical trial design and assay procedures.

Message for the Clinic

The availability and approval of the new oral anticoagulants will impact clinical decision-making for venous thromboembolism prophylaxis. It will be real world experiences that establish how these new drugs will be clinically managed. Practical issues of interactions with prescription and over-the-counter drugs, food and food supplements will need to be properly evaluated and considered for the safety of the treated individuals. Elderly people with long-term comorbid conditions requiring treatment are one large population that can present potential challenges.

Introduction

  1. Top of page
  2. Summary
  3. Review Criteria
  4. Introduction
  5. New and emerging oral anticoagulants
  6. Food interactions
  7. Metabolism
  8. Drug interactions
  9. The potential impact in the US patient population
  10. Conclusion
  11. Author contributions
  12. Acknowledgements
  13. References

The efficacy of venous thromboembolism (VTE) prophylaxis has been well-documented (1), and low-molecular-weight heparin (LMWH) therapy is widely regarded as the standard of care. Vitamin K antagonists (VKAs), such as warfarin, have been the only oral anticoagulants (OACs) approved in the US, despite their limitations (2). VKAs are challenging to use in clinical practice for several reasons, including a narrow therapeutic margin and several food and drug interactions (2). To address these limitations, a new generation of OACs is being developed. The first of these new OACs was ximelagatran, which was approved in Europe, but later withdrawn from market because of safety concerns, particularly liver toxicities. Liver toxicity was not evident after short-term prophylaxis and only became apparent following prolonged (> 35 days) administration (3).

The new and emerging OACs dabigatran etexilate, rivaroxaban and apixaban could offer a rapid onset of action and a predictable anticoagulant effect, as well as facilitating outpatient anticoagulant use. However, whether new OACs have efficacy, safety and pharmacokinetic profiles that are at least non-inferior to the current standard of care has yet to be fully established. Considering the extensive food and drug interactions observed with oral warfarin, caution should be taken in clinical practice with these new OACs. Moreover, the importance of metabolic enzyme pharmacogenomics is emerging as optimisation of warfarin treatment to avoid both over- and under-dosing in individual patients. Thus, the absorption and metabolism of new OACs, and the resulting pharmacokinetic and pharmacodynamical responses in the presence of food and/or other drugs are important considerations for the safety of treated individuals. Here, we discuss the current awareness of food, drug and dietary supplement interactions with these new and emerging OACs, as well as the potential impact these interactions may have among general and special populations.

New and emerging oral anticoagulants

  1. Top of page
  2. Summary
  3. Review Criteria
  4. Introduction
  5. New and emerging oral anticoagulants
  6. Food interactions
  7. Metabolism
  8. Drug interactions
  9. The potential impact in the US patient population
  10. Conclusion
  11. Author contributions
  12. Acknowledgements
  13. References

In Europe and Canada, dabigatran etexilate and rivaroxaban have recently been licensed as orthopaedic surgery thromboprophylaxis (total hip and total knee replacement). Dabigatran etexilate is an oral pro-drug that is rapidly absorbed and converted to the direct thrombin inhibitor, dabigatran (4). Several clinical trials have investigated the efficacy and safety of dabigatran etexilate for VTE prophylaxis in orthopaedic surgery patients (4–8) as well as a recent phase III clinical trial in atrial fibrillation (9). Rivaroxaban and apixaban are selective oral, direct, factor Xa inhibitors. The efficacy and safety of rivaroxaban as VTE prophylaxis in orthopaedic surgery patients (10–15) and as treatment for symptomatic deep-vein thrombosis (DVT) have been investigated (16). US Food and Drug Administration (FDA) approval of rivaroxaban in the orthopaedic surgery setting is not anticipated till late 2009. Apixaban is currently undergoing clinical development. The efficacy and safety of apixaban have been investigated in clinical trials for VTE prophylaxis in orthopaedic surgery patients (17,18) and for the treatment of symptomatic DVT (19). There are little clinical data for apixaban, and current information about its metabolism and potential drug interactions comes largely from preclinical studies.

Food interactions

  1. Top of page
  2. Summary
  3. Review Criteria
  4. Introduction
  5. New and emerging oral anticoagulants
  6. Food interactions
  7. Metabolism
  8. Drug interactions
  9. The potential impact in the US patient population
  10. Conclusion
  11. Author contributions
  12. Acknowledgements
  13. References

Studies have investigated the effect of food on the pharmacokinetics of dabigatran and rivaroxaban using high performance liquid chromatography-tandem mass spectrometry assays (Table 1) (19,20). Following consumption of a high-fat, high-caloric breakfast by 39 healthy subjects aged 18–55 years, there was a delay in the absorption of dabigatran (150 mg), but no difference in the extent of absorption compared with the fasted state (20). In addition, a reduction in inter-individual variability for maximum plasma concentration (Cmax) and area under the drug plasma concentration–time curve (AUC) was noted with the high-fat meal.

Table 1.   Recognised food and drug interactions with the new oral anticoagulants and the population at risk
 Food interactionsMetabolismDrug interactionsPopulation at riskSpecial populations
  1. AIDS, acquired immune deficiency syndrome; AUC, area under the drug plasma concentration–time curve; Cmax, maximum plasma concentration; CYP3A4, cytochrome P450 3A4; HIV, human immune deficiency virus; MRSA, methicillin-resistant Staphylococcus aureus; NSAIDs, non-steroidal anti-inflammatory drugs; PK, pharmacokinetic; P-gp, P-glycoprotein; PT, prothrombin time; TB, tuberculosis; tmax, time to maximum concentration.

DabigatranPK effect  tmax delayed  Cmax and AUC unchanged  Reduced inter-individual variability85% Renal elimination 6% Faecal elimination Metabolised by esterase-catalysed hydrolysis in plasma or liver and P-gp transporter mechanismsCYP3A4 and P-gp inhibitors:  Clarithromycin P-gp inhibitors:  Quinidine, amiodarone, verapamil CYP3A4 and P-gp inducers:  Rifampicin, St. John’s Wort, pantoprazole NSAIDs:  Aspirin, naproxen, diclofenac Antiplatelet agents:  ClopidogrelCardiac arrhythmias Minor depression Bacterial infections (including pharyngitis, tonsillitis, MRSA, TB, meningococcus) Malaria Cluster headaches Gastro-oesophageal reflux disease Cardiovascular disease Pain, fever, and inflammation, including arthritisElderly people Liver disease Renal impairment
RivaroxabanPK effect  tmax delayed  Cmax and AUC increased  Reduced inter-individual variability Pharmacodynamic effect  Increased maximum PT prolongation  Time to maximum PT delayed33% Renal elimination of unchanged drug 33% Renal elimination of drug metabolites 33% Faecal elimination Metabolised by CYP3A4, CYP2J2 and CYP450-independent mechanisms, and P-gp transporter mechanisms in kidneys/intestineCYP3A4 and P-gp inhibitors:  Ketoconazole, itraconazole, voriconazole, posaconazole, ritonavir, clarithromycin CYP3A4 and P-gp inducers:  Rifampicin, St. John’s Wort, phenytoin, carbamazepine, phenobarbitone NSAIDs:  Aspirin, naproxen Antiplatelet agent:  ClopidogrelHIV and AIDS Minor depression Fungal infections Bacterial infections (including pharyngitis, tonsillitis, MRSA, TB, meningococcus) Respiratory tract infections Epilepsy and bipolar disorder Cardiovascular disease Pain, fever, and inflammation, including arthritisElderly people Renal impairment Liver disease
ApixabanNot reported> 46% Faecal elimination 25–28% Renal elimination Metabolised by CYP3A4 mechanisms in liver, and multiple other pathways in kidney/intestineAntiplatelet agent:  ClopidogrelCardiovascular diseaseNot reported

In a pharmacokinetic study of rivaroxaban (20 mg) in 10 healthy young subjects, inter-individual variability for all pharmacokinetic parameters was lower in the fed state, but the presence of food delayed the time to maximum concentration and increased Cmax and AUC (21). Furthermore, there was an increase in maximum prothrombin time (PT)-prolongation (a measure of drug concentration absorbed) from a factor of 1.44 over baseline in the fasting state to 1.53 in the fed state. The type of food, either a high-fat, high-caloric breakfast (= 6) or a high carbohydrate meal (= 4), did not affect the response. Another small study suggested that pH change, using H2-receptor antagonists (ranitidine) or chelating agents, had no effect on the pharmacokinetics of rivaroxaban (22).

At present, there are no published data about food interactions with apixaban.

Metabolism

  1. Top of page
  2. Summary
  3. Review Criteria
  4. Introduction
  5. New and emerging oral anticoagulants
  6. Food interactions
  7. Metabolism
  8. Drug interactions
  9. The potential impact in the US patient population
  10. Conclusion
  11. Author contributions
  12. Acknowledgements
  13. References

Many of the food and drug interactions observed from the wealth of clinical experience with warfarin occur as a result of its metabolic route of clearance, although competition for binding to serum albumin is also responsible. Warfarin clearance is almost entirely hepatic, and the cytochrome (CY)P450 enzyme system mediates its elimination (2). The CYP450 system plays a crucial role in the metabolism of many licensed drugs, and forms a major route of drug clearance (23). CYP450 enzymes are vulnerable to competitive inhibition, which can lead to adverse consequences in drug therapy, including increased toxicity because of reduced drug metabolism, decreased formation of reactive metabolites of pro-drugs resulting in reduced pharmacological effects and drug–drug interactions that cause decreased clearance of one of the drugs when two or more drugs are co-administered. The S enantiomer of warfarin is primarily metabolised by CYP2C9 and the less potent R enantiomer is primarily metabolised by two CYP450 enzymes – CYP1A2 and CYP3A4 (2,23). Warfarin is a moderate inhibitor of CYP2C9 but does not induce or inhibit CYP1A2 or CYP3A4 (24). Consideration should be given to the metabolic clearance of any new drug being developed with the risks and benefits of significant CYP450-mediated metabolism measured. CYP450 enzymes are involved in the metabolism of some of the new OACs, and the possible implications of this are discussed.

Current knowledge regarding the metabolic routes of the new OACs is summarised in Table 1. In vitro experiments have demonstrated that dabigatran is primarily metabolised by esterase-catalysed hydrolysis in the plasma or liver (25). CYP450-mediated metabolism does not play a significant role (25); however, dabigatran acts as a substrate of the efflux transporter P-glycoprotein (26). P-glycoprotein is involved in the transport of many drugs, and therefore can have a significant impact on drug–drug interactions (27). After a single intravenous administration to healthy male subjects, 85% of dabigatran was eliminated in the urine, and faecal excretion accounted for 6% of the administered dose (26).

Two-thirds of rivaroxaban is excreted by the kidneys, with the faecal pathway playing a role in the elimination of the remaining third of the administered dose. Rivaroxaban does not inhibit or induce any major CYP450 enzymes, but two-thirds of the drug is metabolised by CYP3A4, CYP2J2, and CYP450-independent mechanisms before elimination (28). Like dabigatran, rivaroxaban is also a substrate of P-glycoprotein transporters.

The elimination of apixaban involves multiple pathways including renal and faecal excretion (29). In vitro studies have shown that apixaban did not inhibit nor induce major CYP450 enzymes. However, in vitro, the primary metabolite of apixaban was identified as the O-demethylated product, which is formed mainly by CYP3A4 (29,30). More than 46% of apixaban was eliminated via the faecal route, making this the major elimination pathway in humans, while 25–28% was excreted via the kidneys (29).

Drug interactions

  1. Top of page
  2. Summary
  3. Review Criteria
  4. Introduction
  5. New and emerging oral anticoagulants
  6. Food interactions
  7. Metabolism
  8. Drug interactions
  9. The potential impact in the US patient population
  10. Conclusion
  11. Author contributions
  12. Acknowledgements
  13. References

The metabolic route of the new OACs raises concerns for potential interactions with other drugs that are involved with the CYP450 enzyme system or P-glycoprotein transporters. The currently acknowledged drug interactions for the new OACs are listed in Table 1. At this early stage, it is clear that treatment with dabigatran requires caution when combined with strong inhibitors or inducers of P-glycoprotein (26). Concomitant treatment of rivaroxaban with agents that strongly inhibit P-glycoprotein or CYP3A4 is cautioned, and the co-administration of rivaroxaban with drugs that strongly inhibit both P-glycoprotein and CYP3A4 is contraindicated. Apixaban is also metabolised by CYP3A4 and will most likely have similar cautions to those for rivaroxaban when it reaches market. High performance liquid chromatography-tandem mass spectrometry assays have also been used to assess the effect of various drugs on the pharmacokinetics of the new OACs.

Drugs with no clinically relevant interaction

Small studies in healthy subjects have shown that the new OACs do not have any relevant clinical interactions with some common drugs. A clinically relevant interaction between co-administered drugs is one that has a measurable clinical outcome. The level of drug interaction severity can be graded using severity rating scales (31). Typically, the scales grade potential harm to the patient, frequency and predictability of occurrence and the degree and quality of documentation available.

Atorvastatin is a substrate of CYP3A4 and P-glycoprotein; however, its concurrent use with dabigatran (32) was not associated with adverse outcomes in phase I studies. Nevertheless, when atorvastatin and dabigatran were co-administered to 22 healthy young subjects, AUC for dabigatran at steady-state was reduced by 18%, with a concurrent 18% increase in plasma atorvastatin concentration (32). The authors concluded that the observed changes were of little clinical relevance, as there is typically some interindividual variability in the metabolism of atorvastatin. Mild adverse events were dizziness, headache and fatigue. The concentration–effect relationships of dabigatran on activated partial thromboplastin time (aPTT) and ecarin clotting time (ECT) were unaltered (32).

In a study of rivaroxaban in healthy male subjects (n = 38), there was no difference in plasma concentration profiles or steady-state atorvastatin when these drugs were co-administered, and factor Xa inhibition was unaffected (33). Nevertheless, the results of the four phase III RECORD clinical studies showed 23% of patients treated with the combination of rivaroxaban and statins (relative rate 1.52; 95% CI: 1.07–2.17) had major or non-major clinically relevant bleeding in comparison to 18% of patients treated with the LMWH enoxaparin plus statins (relative rate 1.26; 95% CI: 0.81–1.95) (22).

No clinically relevant interaction was noted with dabigatran and digoxin, a P-glycoprotein substrate, in 23 healthy subjects aged 18–65 years (34). When dabigatran and digoxin were co-administered, steady-state Cmax and AUC increased by 7% and 3% respectively, but the plasma concentration of digoxin was unaffected, and the aPTT and ECT were unchanged. Mild adverse events including gastrointestinal and nervous system disorders were reported (34).

In a study of concomitant administration of ranitidine, a weak CYP450 inhibitor, no clinically relevant effect on the extent of dabigatran absorption was observed (26). In a study of rivaroxaban, no significant differences in the plasma concentration profiles, PT prolongation or inhibition of factor Xa activity were noted after co-administration with either ranitidine (n = 12) or antacid (n = 11) to healthy male subjects (35).

Cautioned drugs

There is a bleeding risk associated with the co-administration of an anticoagulant with either an antiplatelet agent or a non-steroidal anti-inflammatory drug (NSAID); the extent of which varies between anticoagulants. Several studies have investigated such interactions with the new OACs. A phase II clinical trial investigated the co-administration of dabigatran and aspirin in patients with atrial fibrillation (n = 502) (36). Major bleeding events occurred in the group treated with high-dose dabigatran (300 mg twice daily) plus aspirin (n = 64), which had a significantly higher rate than the group treated with high-dose dabigatran alone (n = 1050; 4 vs. 0 events respectively; p < 0.02). This high dose is unlikely to be used in clinical practice. The phase III clinical trial in atrial fibrillation evaluated the lower doses of dabigatran 110 or 150 mg twice daily, although bleeding events were not reported according to aspirin use (in approximately 40% of patients) compared with no aspirin use (9). It should also be noted that the highest recommended dosing regimen for dabigatran approved in Europe and Canada for VTE prevention is 220 mg once daily (26).

In a study of rivaroxaban in healthy young male subjects (n = 14), aspirin increased the speed of onset of factor Xa inhibition by approximately 2 h when administered with rivaroxaban, but the level of inhibition was unaffected (35). The combination of rivaroxaban and aspirin led to a slightly greater prolongation of bleeding time than with aspirin alone, although this was not considered clinically significant in this phase I study. Co-administration with aspirin did not substantially alter the pharmacokinetic parameters of rivaroxaban, including the plasma concentration profile, and the inhibitory effect of aspirin on platelet aggregation was unaffected.

A post hoc analysis of pooled data from the four phase III RECORD studies in patients undergoing orthopaedic surgery (n = 12,729) demonstrated that the co-administration of aspirin (or other platelet aggregation inhibitors) or NSAIDs with rivaroxaban did not increase bleeding rate ratios compared with LMWH (37). The efficacy and safety of rivaroxaban vs. placebo were evaluated in 3491 patients with stable, acute coronary syndromes who were also administered either aspirin only (n = 761) or aspirin plus a thienopyridine (n = 2730). The overall risk of clinically significant bleeding with rivaroxaban compared with placebo increased in a dose-dependent manner [hazard ratios 2.21 (95% CI: 1.25–3.91) for 5 mg, 3.35 (95% CI: 2.31–4.87) for 10 mg, 3.60 (95% CI: 2.32–5.58) for 15 mg, and 5.06 (95% CI: 3.45–7.42) for 20 mg doses; p < 0.0001) (38); however, the most common adverse event was chest pain.

In a study of rats administered with clopidogrel or aspirin alone, or both, co-administration with rivaroxaban significantly increased the antithrombotic effect observed with clopidogrel alone (p < 0.01), aspirin alone (p < 0.05) or both (p < 0.001) (39). The addition of rivaroxaban to the combination of clopidogrel plus aspirin produced a small, non-significant prolongation of bleeding time beyond the slight increase observed with all combinations containing clopidogrel. The anticoagulant effect of rivaroxaban, measured by PT, was not influenced by clopidogrel and aspirin alone, or in combination in this preclinical study.

The co-administration of apixaban and aspirin has been investigated in a study in rabbits (40). Compared with apixaban alone, apixaban plus aspirin had a significant additive antithrombotic effect (p < 0.05), which was further enhanced with the addition of clopidogrel (p < 0.05). The combination of clopidogrel plus aspirin with apixaban, significantly increased bleeding time by 2.1-fold compared with control (p < 0.05). In addition, in a phase II dose-ranging study (n = 1715), apixaban has been administered to patients with acute coronary syndromes in combination with aspirin, with or without clopidogrel (41). A dose relationship with bleeding was noted, such that the highest doses of apixaban (10 mg twice daily and 20 mg once daily) were discontinued.

In the case of other analgesics, the FDA analysis identified that the relative rate of major or non-major clinically relevant bleeding with the use of opioids compared with no use was nearly twofold greater with rivaroxaban (2.5) compared with enoxaparin (1.3) (22). This suggests that more research may be warranted regarding the co-medication of rivaroxaban and opioids.

Regarding NSAIDs, the co-administration of dabigatran and a single dose of diclofenac (50 mg) to healthy young subjects (n = 24) reduced the bioavailability of diclofenac and its metabolite as measured by plasma AUC and Cmax, but the same pharmacokinetic parameters of dabigatran were unaffected (42). The authors of this phase I study concluded that these changes were not clinically relevant. There were no differences in the effect of dabigatran on ECT and aPTT with or without diclofenac. When rivaroxaban and the NSAID naproxen were co-administered to 11 healthy male subjects aged 18–45 years, the extent of inhibition of factor Xa activity, the PT and aPTT prolongation were also unaffected, although the effects were delayed (43). The combination of rivaroxaban and naproxen had no effect on platelet aggregation, but bleeding times were significantly increased with the combination compared with rivaroxaban alone (p = 0.017), although the investigators did not regard this as clinically relevant. In the RECORD studies, one death was attributed to the combined effect of rivaroxaban and naproxen (22). An analysis by the US FDA revealed that 53% of patients treated with a combination of rivaroxaban, and an NSAID had major or non-major clinically relevant bleeding (relative rate 1.28; 95% CI: 0.94–1.73) in comparison to 49% of patients treated with the LMWH enoxaparin plus an NSAID (relative rate 0.90; 95% CI: 0.63–1.28); 5% and 4% respectively, for combined treatment with platelet inhibitors (22). The use of both rivaroxaban and dabigatran with NSAIDs is cautioned in product monographs, as some patients may have a greater pharmacodynamic response and increased bleeding risk (26,28).

Dabigatran is poorly soluble above pH 4 and co-administration of dabigatran with pantoprazole, a proton pump inhibitor that increases gastric pH to neutral levels, leads to decreased dabigatran bioavailability (20,44). In both healthy male subjects aged 18–55 years (n = 35) and healthy older individuals aged ≥ 65 years (n = 36), the co-administration of dabigatran and pantoprazole decreased the plasma AUC of dabigatran vs. dabigatran alone (20,44). Pantoprazole and other proton pump inhibitors were, however, co-administered in dabigatran clinical trials and no clinically relevant effects on efficacy and bleeding risk were observed (26).

Amiodarone is a P-glycoprotein inhibitor, and its co-administration with dabigatran increased the AUC and Cmax of dabigatran by approximately 60% and 50% respectively; the extent and rate of absorption of amiodarone were unchanged (26). In the product monograph, it states that in view of the long half-life of amiodarone, the potential for drug interactions may exist for weeks after discontinuation of the drug. It is, therefore, recommended that dosing is reduced to dabigatran 150 mg daily in patients who also receive amiodarone. Rifampicin is a strong inducer of P-glycoprotein and also CYP3A4, and co-administration of rifampicin (600 mg once daily) resulted in a shorter elimination half-life of rivaroxaban, a 50% lower plasma AUC and parallel decreases in the pharmacodynamical effects of rivaroxaban (28), leading to a strong caution for concomitant use.

Contraindicated drugs

At present, the use of dabigatran is contraindicated with quinidine, a potent P-glycoprotein inducer used to treat cardiac arrhythmias and malaria (26). Rivaroxaban is contraindicated in patients receiving systemic HIV-protease inhibitors or azole antimycotics, as they are strong inhibitors of both CYP3A4 and P-glycoprotein (28) (Table 1). The co-administration of rivaroxaban with ketoconazole (400 mg once daily) led to 3.6-fold higher AUC and 1.7-fold higher Cmax of rivaroxaban, as well as significant increases in its pharmacodynamical effects and the potential for increased bleeding risk (28). Similarly, increased pharmacodynamical effects were observed with rivaroxaban plus ritonavir (600 mg twice daily) as a result of a 2.5-fold increase in AUC and a 1.6-fold increase in Cmax (28).

Interaction with other anticoagulants

Although two anticoagulants are traditionally not administered concomitantly, switching between different drugs may be required. Interactions between anticoagulants can have an adverse effect on patient outcomes, particularly with regards to bleeding risk. In addition, there may be interferences in the laboratory assays used for drug monitoring. After combined administration of a single dose of enoxaparin (40 mg) and rivaroxaban (10 mg), an additive effect on anti-factor Xa activity was observed, but there was no effect on clotting tests, and the pharmacokinetics of rivaroxaban were unchanged (28).

Multiple pharmacodynamical interactions of varying intensity were observed when dabigatran, rivaroxaban or apixaban were added to plasma from heparin- or warfarin-treated patients in a study by Masood et al. (45). Heparin plus dabigatran produced a strong additive effect as measured by the aPTT, whereas a weak additive effect was observed with rivaroxaban and apixaban (Figure 1) (45). Warfarin plus each of the new OACs produced an additive effect as measured by the PT (Figure 2) (45). As the new OACs will be used in various thrombotic indications, they may be given in conjunction with VKA and heparins, and the results of Masood et al. demonstrate that this may lead to significant interactions.

image

Figure 1.  The drug interaction anticoagulant response of new oral anticoagulants and heparin was evaluated using an in vitro system. Plasma from patients treated with heparin was collected (n = 30–50) and supplemented with 1 μg/ml of each of drug; activated partial thromboplastin time was then measured (45)

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image

Figure 2.  The drug interaction anticoagulant response of new oral anticoagulants and warfarin was evaluated using an in vitro system. Plasma from patients treated with warfarin was collected (n = 30–50) and supplemented with 1 μg/ml of each drug; prothrombin time was then measured (45)

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The potential impact in the US patient population

  1. Top of page
  2. Summary
  3. Review Criteria
  4. Introduction
  5. New and emerging oral anticoagulants
  6. Food interactions
  7. Metabolism
  8. Drug interactions
  9. The potential impact in the US patient population
  10. Conclusion
  11. Author contributions
  12. Acknowledgements
  13. References

In addition to drug and food interactions, it is equally important to consider liver, kidney and other common disease states that the US population experiences, particularly if these patients have been excluded from clinical trials. The first new OAC, ximelagatran, was withdrawn from market because of concerns over liver toxicity (3). Patients with severe liver disease were excluded from phase III clinical trials evaluating dabigatran, rivaroxaban or apixaban (8,14,16). Additionally, dabigatran and rivaroxaban are contraindicated in patients with severe hepatic impairment (26,28). Nevertheless, the new OACs could, for example, be inadvertently administered to patients with liver disease in whom clinical symptoms are not pronounced; clinical experience in this population is limited. In a phase I study in patients (n = 16) with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, a single dose of apixaban had a consistent and predictable pharmacokinetic and pharmacodynamical profile (46). However, when the new OACs were supplemented to plasma from patients with liver disease, there was a strongly enhanced anticoagulant response as measured by the PT, with a marked increase in the international normalised ratio (INR); apixaban had a lesser effect compared with dabigatran or rivaroxaban (Figure 3A, B) (47). In the aPTT, dabigatran produced a strong effect in prolonging the anticoagulant response, rivaroxaban produced a weaker effect and apixaban did not produce any sizable effect (Figure 3C) (47). This study demonstrated that the new OACs produce marked augmentation of the hypocoagulant effect of liver disease in patients, which varies between patients.

image

Figure 3.  The anticoagulant response of new oral anticoagulants was evaluated in patients with liver disease using an in vitro system. Plasma (n = 10–20) was supplemented with 1 μg/ml of each drug then (A) prothrombin time, (B) international normalised ratio (INR) and (C) activated partial thromboplastin time were measured (47)

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Dabigatran is contraindicated in patients with severe renal impairment, and a reduced dose is recommended in patients with moderate renal impairment (26). Among 18,113 atrial fibrillation patients who were administered dabigatran, 48.4% and 19.4% had mild or moderate renal impairment respectively, but patients with severe renal impairment were excluded (9). Adverse effects among these patients were not reported separately. There is no recommended dose adjustment for rivaroxaban in patients with renal impairment (28). A single 10 mg prophylactic dose was well-tolerated in subjects with severe renal impairment (n = 8), but rivaroxaban plasma concentrations, anti-factor Xa activity and prolongation of PT were all increased with decreasing renal function (48). Population pharmacokinetic/pharmacodynamical models of rivaroxaban in phase II studies of prophylaxis demonstrated an effect of renal function on clearance as well as pharmacodynamical parameters (49). Consideration should, therefore, be given for the impact that hepatic and kidney disease could have on drug metabolism, as subsequent changes in pharmacodynamics or pharmacokinetics could further augment drug interaction effects.

In terms of drug interactions, the escalating use of prescription and over-the-counter (OTC) medications must be considered, as consumption is high among the US adult population. Results of a survey by Qato et al. suggest that approximately half of the population aged 57–85 years taking prescription medication is also concurrently using OTC medications (50). Furthermore, a third of patients regularly use five or more prescription medicines. In the survey, no absolutely contraindicated drug combinations were identified, but several potential major drug–drug interactions were found, including clopidogrel plus warfarin and aspirin plus warfarin (50).

A high proportion of adults in the US consume at least one of the drugs known to have some level of interaction with one of the new OACs. Nearly a third of adults reported aspirin use in a study of the prevalence of medication use in community-dwelling older adults (50). During the year 2000, over 100 billion aspirin tablets were consumed globally for indications including cardiovascular disease, stroke, pregnancy complications, cancer and dementia (51). In addition, aspirin was the second most prescribed drug in 2004 (52). Another large-scale population survey reported that 14% of patients used OTC analgesics (e.g. NSAIDs) a few times a week (53). The prevalence of clopidogrel use is as high as 4% (50), and non-evidence-based prescription of clopidogrel was over 40% in one retrospective cohort study (54). The impact of any drug interactions will only become known with increasing clinical experience of these new OACs. However, the types of drug for which interactions have already been acknowledged may affect several different patient populations.

In general, the elderly population is at increased risk of drug interactions compared with younger individuals, with as many as 1 in 25 older people potentially at risk for a major drug–drug interaction (50). Comorbid illnesses can affect the pharmacokinetics of drugs; more than a third of 65–79-year-olds has at least two comorbid illnesses and this proportion is doubled in those aged ≥ 80 years (55). The efficacy and safety of the new OACs in patients with multiple illnesses have not yet been well studied. As the likelihood of orthopaedic surgery and long periods of immobility is increased in the elderly people, advancing age is an important risk factor for VTE (56). In particular, an ageing population is more likely to suffer from arterial as well as venous thromboembolic disease, highlighting a need for the well-tolerated co-administration of long-term antiplatelet and anticoagulant therapy. Triple antithrombotic therapy, combining dual antiplatelet therapy and an anticoagulant, is likely to become more prominent (57), raising concerns over the increased bleeding risk observed with the new OACs during combined antiplatelet treatment. Half of the older adults in the survey by Qato et al. reported a diagnosis of arthritis (50). Patients suffering from arthritis are typically treated with medications that are either contraindicated or need to be used with caution with the new OACs (Table 1). In addition, elderly people have a higher rate of renal and liver dysfunction, and extremes in body weight compared with the younger population, and they frequently have clinical conditions such as diabetes and thyroid dysfunction. This combination of factors adds to the potential complexity of pharmacokinetic and pharmacodynamical alterations and drug interactions (58).

Cardiovascular disease is widely prevalent, with an estimated one in three people in the US suffering from some manifestation of disease (59). Quinidine and amiodarone are used for the treatment of cardiac arrhythmias, including atrial fibrillation for which the prevalence in people aged older than 80 years is 9% (60). Patients suffering from a cardiovascular disease are typically also treated with medications that are either contraindicated or need to be used with caution with the new OACs (Table 1). Another condition recently associated with increased risk of VTE is infection with HIV (61). With the advances in antiretroviral therapy, the life expectancy of HIV-positive patients has increased, leading to potential complications with the management of other chronic diseases. The interaction of antiretroviral agents and OACs has been reported to increase the difficulty in achieving adequate levels of anticoagulation, as indicated by INR measurements (62). As mentioned, rivaroxaban is contraindicated with the HIV-protease inhibitor, ritonavir (Table 1). HIV patients also suffer from opportunistic infections that are commonly treated with anti-infectives, several of which are either contraindicated or cautioned with rivaroxaban and dabigatran use (Table 1). In addition, concomitant use of rivaroxaban with some medications used to treat epilepsy, such as phenytoin, carbamazepine and phenobarbitone, is cautioned (Table 1). Considering that the prevalence of epilepsy is approximately 0.5% of the US general population (63), such interactions could affect a potentially significant number of people.

There are a number of additional issues that need to be considered regarding the use of new OACs and food and/or drug interactions. Approximately half of the older population taking prescription medication also regularly use dietary supplements (45). Indeed, dietary supplementation with vitamins and minerals is increasingly common in the US (64), and the often unregulated nature of supplements means that potential interactions with new OACs should be considered. Dietary supplements can be advised for the management of cardiovascular diseases, although the risks and benefits are not always clear (65). Herbs and supplements for the prevention and treatment of cardiovascular disease have been associated with adverse effects and interactions. For example, garlic inhibits platelet aggregation and can cause significant anticoagulation, and the Chinese herb danshen (Salvia miltiorrhiza) may potentiate warfarin (65). Grapefruit juice is a strong CYP3A4 inhibitor and may lead to increased exposure of drugs metabolised in this manner (66). At present, however, neither dabigatran nor rivaroxaban is cautioned with grapefruit juice. In addition, the combination of vitamin E and alpha-lipoic acid increases bleeding tendencies (67), which may, for example, interact with long-term anticoagulation. Additionally, St. John’s Wort is one of the most commonly used herbal remedies for minor and major depression. Use of St. John’s Wort often goes unreported to medical practitioners, despite safety concerns about its tendency for clinically relevant drug interactions (68). St John’s Wort induces CYP3A4 and P-glycoprotein (68) and is cautioned with the use of dabigatran and rivaroxaban (Table 1).

The impact of the widespread use of prescription and OTC medications could be further burdened with dosing errors, changing the acceptable safety window in which two drugs can safely be co-administered. Patients who self-medicate with non-prescription analgesics often use more than one product. In a study of 127 patients attending a dental clinic, common use of naproxen (8%) and aspirin (4%) was reported (68). Of these patients, 54% were taking more than one non-prescription analgesic and 14% reported that they exceeded the recommended daily doses, including five patients using naproxen (69). There are also frequent prescribing errors among primary-care practices. In a review of 1879 prescriptions, 7.6% contained a prescribing error, most commonly regarding the frequency (18%) or dose (54%) of a medication (70). The prescription of NSAIDs was the second most common error (7%) after antibiotics (22%).

Real world experience still lacking

Although oral therapy might be more convenient than injections, there is also reduced control over dosing, and patients may frequently either miss doses or take extra doses. In addition, misunderstanding the drug label instructions is common (71). These factors could increase the risk of drug interactions when the therapeutic index of either drug is narrow. Additionally, the extended duration use of these new OACs (e.g. 35 days) increases the possibility of errors. For example, dabigatran is being developed for atrial fibrillation patients and long-term use at higher doses than for VTE prevention (9). Should dabigatran receive a license for this indication, or if any of these drugs are used off-label for long-term needs, the possibilities of errors is further enhanced. The fact that some of these interacting drugs are used to treat potentially life-threatening conditions should not be overlooked. Pharmacokinetic changes can cause concentrations to fall below their therapeutic range, which could aggravate the disease being treated (72). The potential for pharmacogenetical alterations to alter the pharmacokinetics and/or pharmacodynamics of the new OACs, as well as to affect interactions of the new OACs with other drugs and food supplements, is yet to be determined. The majority of drug interaction studies conducted thus far has been in animal models or in healthy subjects, who were all adults. The consequences of increased drug exposure should not be underestimated. Of note, a doubling in dose from the recommended 10 mg dose of rivaroxaban has led to a greater than fourfold increase in major bleeding (4.3% vs. 0.7%) (73). It remains to be seen if any of the interactions deemed not to be clinically relevant in healthy subjects do in fact take on some significance in elderly or sick patients with an altered metabolic capacity.

Conclusion

  1. Top of page
  2. Summary
  3. Review Criteria
  4. Introduction
  5. New and emerging oral anticoagulants
  6. Food interactions
  7. Metabolism
  8. Drug interactions
  9. The potential impact in the US patient population
  10. Conclusion
  11. Author contributions
  12. Acknowledgements
  13. References

Considering the extensive food and drug interactions observed with oral warfarin, caution should be taken in clinical practice with the new OACs, dabigatran, rivaroxaban and apixaban. Several physiological parameters can influence the pharmacokinetic parameters of orally administered drugs, such as changes in gastric pH, intestinal motility and binding; all of which can be affected by concomitant administration of food and/or drugs. At present, the documented food interactions associated with new OACs are few, but there is limited clinical experience at this time. Consideration should be given to the metabolic clearance of these new drugs. The risks and benefits of competition for binding to serum albumin, significant metabolic mechanisms (e.g. CYP450-dependent metabolism) and elimination mechanisms (e.g. P-glycoprotein transporter, kidney function) should be measured. Specifically, dabigatran requires caution when combined with strong inhibitors or inducers of P-glycoprotein. Rivaroxaban, and possibly apixaban, is contraindicated in combination with drugs that strongly inhibit both CYP3A4 and P-glycoprotein, and caution is required when it is used in combination with drugs that are strong inhibitors of only one of these pathways. Important drug interactions of the new OACs that can lead to adverse clinical reactions can occur with NSAIDs, antiplatelet drugs (e.g. aspirin, clopidogrel) and proton pump inhibitors. In particular, there tends to be more clinically relevant bleeding with the concomitant use of the new OACs plus NSAIDs, opioids, statins or nitrates than in those subjects not using these secondary medications. OTC and food supplements (e.g. St. John’s Wort) should not be ignored as they also have interactions with the new OACs. The US population, in general, has a high-frequency of use of OTC medication and supplements, as well as long-term use of drugs for cardiovascular disease, arthritis and other disorders. In addition, the elderly population often has comorbid illnesses and clinical conditions (e.g. diabetes, orthopaedic surgery) that require frequent or long-term drug treatments. Thus, these combinations of factors will add to the complexity of drug interactions in these patient populations.

Many unknowns remain as to how the new OACs will behave in the real world patient population. As evaluations of the new OACs continue, the issue of drug interactions needs to be properly evaluated, particularly as some of the interacting drugs are used to treat potentially life-threatening conditions. The new OACs offer significant potential advantages to the field of VTE prophylaxis, but their lack of extensive clinical experience should not be underestimated. The issues surrounding the market withdrawal of ximelagatran have demonstrated that safety profiles in particular cannot be extrapolated from different regimens, such as short-term prophylaxis.

Author contributions

  1. Top of page
  2. Summary
  3. Review Criteria
  4. Introduction
  5. New and emerging oral anticoagulants
  6. Food interactions
  7. Metabolism
  8. Drug interactions
  9. The potential impact in the US patient population
  10. Conclusion
  11. Author contributions
  12. Acknowledgements
  13. References

Concept/design, JMW; data analysis/interpretation, JMW, CA; drafting article, JMW; critical revision of article, JMW, CA; approval of article, JMW, CA; data collection, CA.

Acknowledgements

  1. Top of page
  2. Summary
  3. Review Criteria
  4. Introduction
  5. New and emerging oral anticoagulants
  6. Food interactions
  7. Metabolism
  8. Drug interactions
  9. The potential impact in the US patient population
  10. Conclusion
  11. Author contributions
  12. Acknowledgements
  13. References

The authors received editorial/writing support in the preparation of this manuscript funded by sanofi-aventis U.S., Inc. Anne Ozog, PhD, provided the editorial/writing support. The authors were fully responsible for all content and editorial decisions and received no financial support or other form of compensation related to the development of the manuscript.

References

  1. Top of page
  2. Summary
  3. Review Criteria
  4. Introduction
  5. New and emerging oral anticoagulants
  6. Food interactions
  7. Metabolism
  8. Drug interactions
  9. The potential impact in the US patient population
  10. Conclusion
  11. Author contributions
  12. Acknowledgements
  13. References